Article Text

Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program
  1. RAINBO Research Consortium
  1. Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to RAINBO Research Consortium, Leiden University Medical Center, Leiden, Netherlands; n.horeweg{at}lumc.nl

Abstract

Background The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer.

Primary Objective(s) The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation.

Study Hypothesis Molecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation.

Trial Design The RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I–III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I–III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility.

Major Inclusion/Exclusion Criteria Inclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm.

Primary Endpoint(s) Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial.

Sample Size The p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600.

Estimated Dates for Completing Accrual and Presenting Results The four clinical trials will have different completion dates; main results are expected from 2028.

Trial Registration Number The RAINBO program is registered at clinicaltrials.gov (NCT05255653).

  • endometrial neoplasms
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Twitter @RAINBOprogram

  • Collaborators RAINBO Research Consortium: Individual names of the members of the collaborator group: Steering Group (alphabetical): T Bosse,1 CL Creutzberg,2 EJ Crosbie,3 K Han,4 N Horeweg,2 A Leary,5 JR Kroep,6 JN McAlpine,7 ME Powell.8 Translational Committee (alphabetical): F Blanc-Durand,5 T Bosse,1 M de Bruyn,9 DN Church,10,11 N Horeweg,2 VH Koelzer,12,13 S Kommoss,14 A Leary,5 JN McAlpine,7 N Singh.15 Statistical Committee (alphabetical): A Bardet,16,17 N Counsell,18 N Horeweg,2 H Putter,19 D Tu.20 Advisory Committee (alphabetical): R Edmondson,3 C Gordon,21 J Ledermann,22 P Morice,23 H MacKay,24 H Nijman,9 RA Nout,25 VTHBM Smit,1 H White.26 Country Champions (alphabetical): J Alexandre,27,28 SM de Boer,2 I Boere,29 R Cooper,30 JL Ethier,31,32 JS Frenel,33 J McGrane,34 A Taylor,35 S Welch,36 AM Westermann.37 Trial Management (alphabetical): H Dijcker-van der Linden,38 L Farrelly,18 A Feeney,18 M Kaya,2 W Liu,20 A Melis,38 F Ngadjeua-Tchouatieu,39 W Parulekar,20 K Verhoeven-Adema.38 Writing Committee: N Horeweg,2 ME Powell,8 K Han,4 JR Kroep,6 F Blanc-Durand,5 S Welch,34 A Bardet,16,17 N Counsell,18 H Putter,19 D Tu,20 N Singh,15 DN Church,10,11 S Kommos,14 M de Bruyn,9 H Nijman,9 CL Creutzberg,2 JN McAlpine,7 T Bosse,1 EJ Crosbie,3 H MacKay,23 A Leary.5 Affiliations of the participants of the RAINBO research consortium: 1Department of Pathology, Leiden University Medical Center, the Netherlands. 2Department of Radiation Oncology, Leiden University Medical Center, the Netherlands. 3Department of Obstetrics and Gynaecology, Manchester Academic Health Science Centre, St Mary’s Hospital, Manchester, UK. 4Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Radiation Oncology, Toronto, Canada. 5Department of Medical Oncology, Gustave Roussy Cancer Center, Université Paris Saclay, Cancer Medicine and Gynecological Tumor Translational Research Lab, Villejuif, France. 6Department of Medical Oncology, Leiden University Medical Center, the Netherlands. 7Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada. 8Department of Clinical Oncology, Barts Health NHS Trust, London, UK. 9Department of Gyneacology, University Medical Center Groningen, Groningen University, Groningen, the Netherlands. 10Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 11Oxford NIHR Comprehensive Biomedical Research Centre, Oxford, UK. 12Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland. 13Department of Oncology and Nuffield Department of Medicine, University of Oxford, Oxford, UK. 14Department of Women’s Health, University of Tübingen, Tübingen, Germany. 15Department of Cellular Pathology, Barths Health NHS Trust, London, UK. 16Bureau of Biostatistics and Epidemiology, University Paris-Saclay, Gustave-Roussy, Villejuif, France. 17Oncostat U1018, Inserm, University Paris-Saclay, Ligue Contre le Cancer, Villejuif, France18. Cancer Research UK and University College London Cancer Trials Centre, University College London, London, UK. 19Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands. 20Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada. 21Patient Representative, Canadian Cancer Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada. 22Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute and UCL Hospitals, London, UK. 23Department of Gynaecologic Surgery, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France. 24Department of Medical Oncology, Odette Cancer Center, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 25Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 26Patient Representative, Peaches Patient Voices, Manchester, UK. 27Centre de Recherche des Cordeliers, Equipe labélisée Ligue Contre le Cancer, Sorbonne Université, Université de Paris, INSERM, Paris, France. 28Department of Medical Oncology, Hopital Cochin, Institut du Cancer Paris, Paris, France. 29Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 30Department of Clinical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. 31Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Kingston, Ontario, Canada. 32Department of Oncology, Queen’s University, Kingston, Ontario, Canada. 33Department of Medical Oncology, Institut de Cancerologie de l’Ouest-Centre Rene Gauducheau, Saint-Herblain, France. 34Sunrise Oncology Centre, Royal Cornwall Hospital, Truro, UK. 35Department of Gynaecological Oncology, The Royal Marsden NHS Foundation Trust, London, UK. 36Division of Medical Oncology, Western University, London, Ontario, Canada. 37Department of Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands. 38Comprehensive Cancer Center the Netherlands (IKNL), Leiden, the Netherlands. 39Clinical Research Department, Institute Gustave Roussy, Chevilly-Larue, France.

  • Contributors The current work is the result of the collaborative effort of the RAINBO Research Consortium. The Consortium is led by the Steering Group consisting of the following members (in alphabetical order): T Bosse, CL Creutzberg, EJ Crosbie, K Han, N Horeweg, A Leary, JR Kroep, JN McAlpine, ME Powell. The Translational Committee is responsible for the design and conduct of translational studies with the tumor materials obtained from the participants of the RAINBO program and consists of the following members (in alphabetical order): F Blanc-Durand, T Bosse, M de Bruyn, DN Church, N Horeweg, VH Koelzer, S Kommoss, A Leary, JN McAlpine, N Singh.The Statistical Committee is responsible for the design and analyses of the outcomes of the four RAINBO clinical trials and the overarching research program and consists of the following members (in alphabetical order): A Bardet, N Counsell, N Horeweg, H Putter, D Tu. The Advisory Committee with representation from international experts and patient advocates provides the Steering Group with independent advice and consists of the following members (in alphabetical order): R Edmondson, C Gordon, J Ledermann, P Morice, H MacKay, H Nijman, RA Nout, VTHBM Smit, H White.The Country Champions are responsible for the execution of the RAINBO clinical trials in the non-leading countries (in alphabetical order): J Alexandre, SM de Boer, I Boere, R Cooper, JL Ethier, JS Frenel, J McGrane, A Taylor, S Welch, AM Westermann. The RAINBO clinical trials are managed by (in alphabetical order): H Dijcker-van der Linden, L Farrelly, A Feeney, M Kaya, W Liu, A Melis, F Ngadjeua-Tchouatieu, W Parulekar, K Verhoeven-Adema. The current manuscript has been written collaboratively by all the Writing Committee members: N Horeweg, ME Powell, K Han, JR Kroep, F Blanc-Durand, S Welch, A Bardet, N Counsell, H Putter, D Tu, N Singh, DN Church, S Kommos, M de Bruyn, H Nijman, CL Creutzberg, JN McAlpine, T Bosse, EJ Crosbie, H MacKay, A Leary. NH acts as guarantor for this publication and takes responsibility for its content. The sponsors are responsible for the conduct of the clinical trials of the RAINBO program.

  • Funding A research project grant from the Dutch Cancer Society (KWF 13403) was awarded for partial funding of the MMRd-GREEN trial and the RAINBO overarching research program. An unrestricted educational grant from the French Institut National du Cancer was awarded for partial funding of the p53abn-RED trial and French participation in the RAINBO program. An unrestricted educational grant was provided by AstraZeneca for partial funding of the p53abn-RED trial. Two grants from the Canadian Institutes for Health Research were awarded for, respectively, the POLEmut-BLUE trial (CCTG EN.10 TAPER arm A POLE) and Canadian participation in the MMRd-GREEN trial. Durvalumab and olaparib were provided by AstraZeneca.

  • Competing interests J Alexandre reports grants paid to his institution by MSD and Janssen; consulting fees to him by MSD, AstraZeneca, GSK, Eisai, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to him by MSD, AstraZeneca, GSK, Clovis, and Novartis; support for attending meetings and/or travel to him by AstraZeneca and Novartis. SM de Boer reports a research grant paid to her institution by Varian Medical Systems. T Bosse reports research project funding by the Dutch Cancer Society (KWF). DN Church has participated in an advisory board for MSD and has received research funding from HalioDx (on behalf of the TransSCOT consortium). CL Creutzberg reports research grants from the Dutch Cancer Society (KWF) for the conduct of the PORTEC trials and the RAINBO program. JL Ethier reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events by Merck, GSK and AstraZeneca and participation in these companies’ Advisory Boards. JS Frenel reports having personally received consulting fees and support for attending meetings and/or travel by Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagan. Payment or honoraria were personally received for lectures, presentations, speaker bureaus, manuscript writing or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen. C Gordon reports being a member of the Canadian Cancer Clinical Trials Group as member of the Patients’ Representatives Committee on a volunteer basis. K Han reports research grants from the Canadian Institutes of Health Research Project Grant and Princess Margaret Hospital Foundation, participating on the Astra Zeneca Cervical Cancer Radiation Oncology Advisory Board (October 2021), and being Endometrial Cancer Working Group Co-Chair of the Canadian Cancer Trials Group. N Horeweg reports research grants paid to her institution from the Dutch Cancer Society (KWF) and an unrestricted research grant by Varian for the RAINBO program and other unrelated research projects. VH Koelzer is principal investigator in a public-private partnership with Roche unrelated to the topic of this manuscript, received research funding from the Image Analysis Group unrelated to the topic of this manuscript, served as an invited speaker on behalf of Indica Labs, and is participant of a patent application co-owned by the Netherlands Cancer Institute (NKI-AVL) and the University of Basel on the assessment of cancer immunotherapy biomarkers by digital pathology. JR Kroep reports having received study drugs and an unrestricted research grant from AstraZeneca for the conduct of the MMRd-GREEN trial, as well as a research grants from the Dutch Cancer Society and WCRF. Consulting fees were paid to the researcher’s institution by AstraZeneca, MSD, GSK, Novartis and Eisai, as well as payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events by MSD and GSK. Participation on a Data Safety Monitoring Board or Advisory Board without payment for the TEIPP trial and the ALISON trial were reported. J McGrane reports having received consulting fees for participation in advisory boards of GSK, MSD and Ipsen and honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, and for attending meetings and/or travel. A Taylor reports participation in the advisory board of MSD.

  • Provenance and peer review Commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.