Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Carboplatin

Doxorubicin

Liposomal doxorubicin

Albumin-Bound Paclitaxel

Cisplatin

Establishment of molecular-clinicopathological classification to make adjuvant treatment decisions: observation for favourable group; vaginal brachytherapy(VBT) for intermediate group; external beam radiotherapy(EBRT) for unfavourable group.

Molecular-clinicopathological classification strategy：Favourable group：POLE-mutated. CTNNB1(wide-type)with IA (G1-3) or IB(G1-2)and LVSI(lymph-vascular space invasion) focal/-.

Intermediate group：MMRD and LVSI focal/-. CTNNB1(wide-type) and IB(G3) or II with LVSI focal/-. CTNNB1-mutated and IA(G1-3) or IB (G1-2) with LVSI focal/-.

Unfavourable group: TP53 mutation. CTNNB1-mutated and IB (G3) or II. Substantial LVSI.

Adjuvant vaginal brachytherapy alone for intermediate risk patients (IA G1-2 with LVSI present or age\>60, IA G3 or IB G1-2 regardless of LVSI status).

EBRT for high-intermediate risk (stage I B with G3, or stage II)

High-dose rate vaginal brachytherapy (VBT) was delivered with a vaginal cylinder.For VBT administered alone, the dose is recommended: 3 fractions of 7 Gy or 5 fractions of 6 Gy or 6 fractions of 5 Gy.

For VBT administered after completion of EBRT: 2-3 fractions of 4-6 Gy.

Vaginal brachytherapy

EBRT was delivered to the pelvic area using a total dose of 45-50.4Gy in 25-28 fractions over 5-6 weeks with the intensity-modulated radiotherapy (IMRT) technique, three-dimensional conformal radiotherapy (3D-CRT) modality

Pelvic external beam radiotherapy

No radiotherapy is administrated, but active follow-up and quality of life questionnaires is needed after surgery.

Observation

Intravenous concurrent or sequential adjuvant chemotherapy consists of carboplatin/paclitaxel, cisplatin/doxorubicin or cisplatin/doxorubicin/paclitaxel, etc.

Chemotherapy

Xiaorong Hou, PhD

The purpose of this study is to compare the efficacy and toxicity of early stage endometrial cancer based on molecular classification and conventional risk stratification adjuvant therapy decision-making, and to provide high-quality evidence-based medical evidence for individualized adjuvant therapy selection under the guidance of fine stratification system of endometrial cancer.

This is an investigator-initiated prospective, national multicentre, phase III, randomised, open, non-inferiority clinical study. The study hypothesis is that adjuvant radiotherapy decision for early-stage endometrial cancer which is based on molecular classification can achieve de-escalation of adjuvant treatment without reducing local tumour control and survival, thereby potentially further reducing radiotherapy-related toxicity and improving quality of life, compared to using conventional risk stratification. The primary endpoint of this study is the 3-year local recurrence rate.

Study of Early Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions

A Prospective Multicentre Phase III Randomised Open Clinical Study of Early Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions

Loco-regional recurrence (LRR) is defined as the first recurrence in the vagina or pelvic cavity during follow-up, which was confirmed by imaging examination or biopsy pathology.

FFS is defined as the time from randomization to recurrence,distant metastasis or death from any cause,whichever is first.

Overall survival is calculated from randomization to death from any cause.

Recurrence in the vaginal area during follow-up

Recurrence in the pelvic area, including the vagina, during follow-up

Distant metastasis (such as bone, lung, liver, brain, non-pelvic regional lymph node metastasis).

Comparison of the proportion of patients in two groups with the same clinicopathologic factors (FIGO, G, LVSI, age) downgraded from EBRT to VBT or from adjuvant radiotherapy (EBRT or VBT) to observation.

General quality of life and general cancer related symptoms is accessed by Quality of Life Core Questionnaire (QLQC-30), ,scored as quite a bit/very much vs no or mild symptoms

Acute radiation enteritis, radiation cystitis, radiation lymphopenia, late radiation enteritis, radiation cystitis, vaginal stenosis or shortening, lymphedema, bone marrow suppression according to CTCAE v 5.0.

All hospital based health care costs used with primary treatment or during follow-up for treatment of adverse events and/or treatment for relapse.

Xijing Hospital, Air Force Medical University of PLA

The Second Affiliated Hospital of Dalian Medical University

The second hospital Affiliated by Jilin University

First Affiliated Hospital Xi'an Jiaotong University

The Affiliated Hospital of Inner Mongolia Medical University

Third Affiliated Hospital of Xinjiang Medical University

Peking University First Hospital

The 940th Hospital of Joint Logistics Support Force，PLA.

Xiangya Hospital of Central South University

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Peking Union Medical College Hospital

Reproductive Control Agents

Central Nervous System Stimulants

Herbal and Botanical

Durvalumab

Olaparib

Megestrol

Megestrol Acetate

Progestins

Medroxyprogesterone Acetate

Medroxyprogesterone

Antineoplastic Agents, Immunological

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Contraceptive Agents

Contraceptives, Oral

Contraceptives, Oral, Hormonal

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Contraceptive Agents, Male

Antineoplastic Agents, Hormonal

Hormones

Hormone Antagonists

Orange

Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for two years

Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)

Adjuvant pelvic external beam radiotherapy

Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years

No adjuvant therapy in women with:

* stage IA (not confined to polyp), grade 3, pN0, with or without LVSI
* stage IB, grade 1 or 2, pNx/N0, with or without LVSI
* stage IB, grade 3, pN0, without substantial LVSI
* stage II (microscopic), grade 1 or 2, pN0, without substantial LVSI

No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with:

* stage IA (not confined to polyp), grade 3, pNx, with or without LVSI
* stage IB, grade 3, pNx, with or with LVSI.
* stage IB, grade 3, pN0, with substantial LVSI.
* stage II (microscopic), grade 1 or 2, pNx, with or without LVSI.
* stage II (microscopic), grade 1 or 2, pN0, with substantial LVSI.
* stage II (microscopic), grade 3, pNx/N0, with or without LVSI.
* stage II non-microscopic, any grade, pNx/N0, with or without LVSI.
* stage III, any grade, pNx/N0-2, with or without LVSI.

45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week

Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.

1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,

Oral medroxyprogesterone acetate for two years

Vaginal brachytherapy is to be considered in patients with documented cervical stromal involvement and/or substantial LVSI. Brachytherapy is given with a vaginal cylinder or vaginal ovoids or ring applicator, according to the center's standard technique. When using a cylinder, the active length will ideally be 2-3 cm, with the reference isodose covering the proximal 2.5-3 cm of the vagina. High-dose-rate (HDR) and pulse-dose-rate (PDR) schedules are permitted, which deliver an EQD2 equivalent dose of 10-14 Gy at 5 mm from the vaginal mucosa (to obtain a cumulative EDQ2 of 60 Gy at 5 mm).

Carien L Creutzberg, MD PhD

Nanda Horeweg, MD PhD

Kathy Han, MD PhD

Jessica N McAlpine, MD PhD

Alexandra Leary, MD PhD

Anneke M Westermann, Md PhD

Joan Heijns, MD PhD

Frederieke Koppe

Mandy Kiderlen, Md PhD

Annemarie Thijs

A Wymenga, MD PhD

Ann KL Reyners, MD PhD

Judith R Kroep, MD PhD

Merve Kaya, MD

Ingrid Boere, Md PhD

Melanie E Powell, MD PhD

Emma J Crosbie, MD PhD

Alexandra Leary, Md PhD

Melanie E Powell, Md PhD

Emma J Crosbie, Md PhD

Kathy Han, Md PhD

Jessica N McAlpine, Md PhD

The RAINBO umbrella program consists of four clinical trials investigating new adjuvant therapies in endometrial cancer patients. Eligible patients will be assigned to one of the four RAINBO trials based on the molecular profile of their cancer:

* p53 abnormal endometrial cancer patients to the p53abn-RED trial
* mismatch repair deficient endometrial cancer patients to the MMRd-GREEN trial
* no specific molecular profile endometrial cancer patients to NSMP-ORANGE trial
* POLE mutant endometrial cancer patients to the POLEmut-BLUE trial

The p53abn-RED trial (NCT05255653-1) is an international, multicenter, phase III randomised trial wherein adjuvant chemoradiation followed by olaparib for two years is compared to adjuvant chemoradiation.

The MMRd-GREEN trial (NCT05255653-2) is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy combined with and followed by durvalumab for one year is compared to adjuvant pelvic external beam radiotherapy.

The NSMP-ORANGE trial (NCT05255653-3) is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy followed by progestogens for two years is compared to adjuvant chemoradiation.

The POLEmut-BLUE trial (NCT05255653-4) is an international, multicenter, single arm, phase II trial wherein safety of de-escalation of adjuvant therapy is investigated: no adjuvant therapy for stage I-II disease and no adjuvant therapy or pelvic external beam radiotherapy only for stage III disease.

The overarching RAINBO research project will combine the data and tumor material of the four RAINBO clinical trials to perform translational research and compare molecular profile-based adjuvant therapy to standard adjuvant therapy in terms of effectiveness, toxicity, quality of life and cost utility.

Umbrella trial wherein eligible patients are assigned to one of four parallel running clinical trials. Three of four trials are randomised controlled trials and one is a prospective clinical trial with two study arms.

Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features

Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features: the p53abn-RED Trial, the MMRd-GREEN Trial, the NSMP-ORANGE Trial and the POLEmut-BLUE Trial

Following the planned translational work in the RAINBO programme and publications, the translational research (TR) committee will open up the sample collection to external researchers. Access will be granted following completion of a research proposal form and approval by the TR committee chaired by Dr. Tjalling Bosse. All external researchers will be expected to demonstrate funding for their project and ethics approval. Data will be made available as required through data sharing agreements. The following will be reviewed when considering applications for data sharing and sample access: data and sample use is in-keeping with patient consent, the proposed project has scientific value, with defined objectives and study plan, trial data are appropriate for the intended purpose, acknowledgement of the RAINBO Programme in all publications that arise from the data sharing, compliance with legal and regulatory requirements as applicable and patient confidentiality maintained at all times.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Early Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions	NCT05524389	Endometrial Can... Adjuvant Radiot... Molecular Class...	Vaginal brachyt... Pelvic external... Observation Chemotherapy	18 Years - 75 Years	Peking Union Medical College Hospital
Study of Early Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions	NCT05524389	Endometrial Can... Adjuvant Radiot... Molecular Class...	Vaginal brachyt... Pelvic external... Observation Chemotherapy	18 Years - 75 Years	Peking Union Medical College Hospital
Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features	NCT05255653	Endometrial Can...	Olaparib Pelvic external... Chemotherapy Durvalumab Medroxyprogeste... Megestrol Aceta... Vaginal brachyt... Observation	18 Years -	Leiden University Medical Center

Spots Global Cancer Trial Database for pelvic external beam radiotherapy