Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: Olaparib
* Radiation: Pelvic external beam radiotherapy
* Drug: Chemotherapy
* Drug: Durvalumab
* Drug: Medroxyprogesterone Acetate
* Drug: Megestrol Acetate
* Radiation: Vaginal brachytherapy
* Other: Observation


Participation Criteria
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Eligibility Criteria
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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. Exclusion Criteria overarching RAINBO program: History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years Prior pelvic radiation The p53abn-RED trial Inclusion criteria: p53 abnormal EC Histologically confirmed stage I (with invasion) II or III EC WHO Performance score 0-1 Body weight > 30 kg Adequate systemic organ function: Creatinine clearance (> 40 cc/min): Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. Adequate bone marrow function : hemoglobin >9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l. Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician, AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN Exclusion criteria: Pathogenic POLE mutation(s) Mismatch repair deficiency Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP History of allogenic organ transplantation Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent Any previous treatment with a PARP inhibitor, including olaparib History of active primary immunodeficiency History or evidence of hemorrhagic disorders within 6 months prior to randomization Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT) Active infection, including: tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent. The MMRd-GREEN trial Inclusion criteria: Mismatch repair deficient EC Histologically confirmed Stage III EC or stage IB/II EC with substantial lympovascular space invasion (LVSI) WHO Performance score 0-1 Body weight > 30 kg Adequate systemic organ function: Creatinine clearance (> 40 cc/min): Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. Adequate bone marrow function : hemoglobin >9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l. Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). <<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.>> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN Exclusion criteria: Pathogenic POLE mutation(s) Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational medicinal product (IMP) History of allogenic organ transplantation Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. Any previous treatment with a PD(L)1 inhibitor, including durvalumab. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IMP. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with the exceptions of: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection). Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). History of active primary immunodeficiency Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the study physician. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent. The NSMP-ORANGE trial Inclusion criteria: NSMP EC Histologically confirmed stage II EC with substantial LVSI or stage III EC ER positive EC WHO performance status 0-1 Exclusion criteria: Pathogenic POLE mutation(s) Mismatch repair deficiency p53 abnormality The POLEmut-BLUE trial Inclusion criteria: Pathogenic POLE mutation(s) For the main cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI: 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 For the exploratory cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI: 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. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures. Patient is able (i.e., sufficiently fluent) and willing to complete the QOL and/or health utility questionnaires in either English, French or a validated language. The baseline assessment must be completed within the required timelines, prior to enrolment. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial. In accordance with CCTG policy, protocol treatment is to begin within 10 weeks of hysterectomy/bilateral salpingo-oophorectomy. Exclusion criteria: Prior chemotherapy for EC Isolated tumor cells identified in lymph node(s) for main study cohort (patient can be included in exploratory cohort)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: p53abn-RED trial: experimental<br>Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for two years | Drug: Olaparib<br>* 300 mg twice daily for two years<br>* Other names: Lynparza;Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Drug: Chemotherapy<br>* 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.<br>* Other names: Paclitaxel;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Active Comparator: p53abn-RED trial: control<br>Adjuvant radiotherapy and chemotherapy | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Drug: Chemotherapy<br>* 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.<br>* Other names: Paclitaxel;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Experimental: MMRd-GREEN trial: experimental<br>Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Drug: Durvalumab<br>* 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,<br>* Other names: Imfinzi;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Active Comparator: MMRd-GREEN trial: control<br>Adjuvant pelvic external beam radiotherapy | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Experimental: NSMP-ORANGE trial: experimental<br>Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Drug: Medroxyprogesterone Acetate<br>* Oral medroxyprogesterone acetate for two years<br>* Other names: Progestogen;Drug: Megestrol Acetate<br>* Oral medroxyprogesterone acetate for two years<br>* Other names: Progestogen;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Active Comparator: NSMP-ORANGE trial: control<br>Adjuvant radiotherapy and chemotherapy | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Drug: Chemotherapy<br>* 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.<br>* Other names: Paclitaxel;Radiation: Vaginal brachytherapy<br>* 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).<br>|
| Other: POLEmut-BLUE trial: main cohort<br>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 | Other: Observation<br>* No adjuvant therapy<br>|
| Other: POLEmut-BLUE trial: exploratory cohort<br>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. | Radiation: Pelvic external beam radiotherapy<br>* 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week<br>* Other names: EBRT;Radiation: Vaginal brachytherapy<br>* 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).<br>Other: Observation<br>* No adjuvant therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| p53abn-RED trial | Recurrence-free survival | 3 years | 
| MMRd-GREEN trial | Recurrence-free survival | 3 years | 
| NSMP-ORANGE trial | Recurrence-free survival | 3 years | 
| POLEmut-BLUE trial | Pelvic recurrence-free survival | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival | All RAINBO trials | 5 years | 
| Pelvic recurrence-free survival | All RAINBO trials | 5 years | 
| Vaginal recurrence-free survival | All RAINBO trials | 3 years, 5 years | 
| Endometrial cancer-specific survival | All RAINBO trials | 3 years, 5 years | 
| Overall survival | All RAINBO trials | 3 years, 5 years | 
| Treatment-related toxicity - according to CTCAE v5.0 | All RAINBO trials | 3 years, 5 years | 
| Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire | All RAINBO trials | 3 years, 5 years | 
| Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire | All RAINBO trials | 3 years, 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MMRd, NSMP, POLE, Endometrial Cancer, Molecular risk factors, Olaparib, Durvalumab, Progestagens, Chemoradiation, Radiotherapy, Observation, p53