Endometrial Cancer
Conditions
Keywords
Endometrial Cancer, Molecular risk factors, Olaparib, Durvalumab, Progestagens, Chemoradiation, Radiotherapy, Observation, p53, MMRd, NSMP, POLE
Brief summary
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
Detailed description
The p53abn-RED trial (NCT05255653-1) is an international, multicenter, phase III randomised trial wherein adjuvant chemoradiation followed by olaparib for one year 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 with or without chemotherapy. 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.
Interventions
DRUGDurvalumab
1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,
DRUGMedroxyprogesterone Acetate
Oral medroxyprogesterone acetate for two years
DRUGMegestrol Acetate
Oral medroxyprogesterone acetate for two years
DRUGOlaparib
300 mg twice daily for one year
RADIATIONPelvic external beam radiotherapy
45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
DRUGChemotherapy
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.
RADIATIONVaginal brachytherapy
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).
OTHERObservation
No adjuvant therapy
Sponsors
Leiden University Medical Center
Institute Gustave Roussy (sponsor p53abn-RED trial)
Leiden University Medical center (sponsor MMRd-GREEN trial)
University College London (sponsor NSMP-ORANGE trial)
Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial)
Dutch Gynaecological Oncology Group
Comprehensive Cancer Centre The Netherlands
Cancer Research UK & UCL Cancer Trials Centre
Dutch Cancer Society
AstraZeneca
National Cancer Institute, France
Canadian Institutes of Health Research (CIHR)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Platform 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants of the four RAINBO trials should be eligible according to the inclusion and
Exclusion criteria
of both the overarching RAINBO trials program and the clinical trial that they are assigned to based on the molecular profile. Inclusion Criteria of the overarching RAINBO program: * Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of the aforementioned histotypes. * Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020) * Hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery * No distant metastases as determined by pre-surgical or post-surgical imaging (CT scan of chest, abdomen and pelvis or whole-body PET-CT scan) * WHO performance status 0, 1 or 2 * Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery * Patients must be accessible for treatment and follow-up * Written informed consent for participation in one of the RAINBO trials, permission for the contribution of a tissue block for translation research and permission for the use and sharing of data for the overarching research project according to the local Ethics Committee requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| p53abn-RED trial | 3 years | Recurrence-free survival |
| MMRd-GREEN trial | 3 years | Recurrence-free survival |
| NSMP-ORANGE trial | 3 years | Recurrence-free survival |
| POLEmut-BLUE trial | 3 years | Pelvic recurrence-free survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free survival | 5 years | All RAINBO trials |
| Pelvic recurrence-free survival | 5 years | All RAINBO trials |
| Vaginal recurrence-free survival | 3 years, 5 years | All RAINBO trials |
| Endometrial cancer-specific survival | 3 years, 5 years | All RAINBO trials |
| Overall survival | 3 years, 5 years | All RAINBO trials |
| Treatment-related toxicity - according to CTCAE v5.0 | 3 years, 5 years | All RAINBO trials |
| Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire | 3 years, 5 years | All RAINBO trials |
| Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire | 3 years, 5 years | All RAINBO trials |
Countries
Canada, France, Netherlands, United Kingdom
Contacts
CONTACTCarien L Creutzberg, MD PhD
CONTACTNanda Horeweg, MD PhD
PRINCIPAL_INVESTIGATORAlexandra Leary, Md PhD
Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)
PRINCIPAL_INVESTIGATORJudith R Kroep, MD PhD
Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)
PRINCIPAL_INVESTIGATORMelanie E Powell, Md PhD
Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)
PRINCIPAL_INVESTIGATOREmma J Crosbie, Md PhD
St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)
PRINCIPAL_INVESTIGATORKathy Han, Md PhD
Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)
PRINCIPAL_INVESTIGATORJessica N McAlpine, Md PhD
University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)
Outcome results
None listed