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

• 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.

• 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

• Mismatch repair deficient EC

• Histologically confirmed (FIGO 2009) stage IB/II EC with myometrial or cervical stroma involvement and lympovascular space invasion (LVSI) OR Stage III EC OR Stage IVA with limited pelvic peritoneal involvement

• 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

• NSMP EC

• Histologically confirmed stage II EC with substantial LVSI or stage III EC

• ER positive EC

• WHO performance status 0-1

• 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 - Stage III not included in main cohort

⁃ Multiple molecular classifiers stage IA (not confined to polyp), grade 3 - Stage III

• 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.