Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO) - NSMP-ORANGE Trial: Comparing Radiotherapy With Oral Progestin Tablets vs. the Current Standard Care, Radiotherapy and Chemotherapy, in Patients With NSMP Endometrial Cancer

Prior treatment

• Prior pelvic radiation
• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) within previous 6 months
• Thromboembolic event, e.g. pulmonary embolism or deep vein thrombosis, within previous 6 months
• Patients who have received a live attenuated vaccine within 2 weeks prior to planned treatment start
• The patient is currently participating in another interventional clinical trial or has received an investigational drug (either approved or not approved) in any prior clinical study within 5 half-lives prior to screening

Other illness

• Previous malignancy, except for non-melanoma skin cancer, in the past 5 years
• Uncontrolled cardiac disease (defined as cardiac function which would preclude hydration during cisplatin administration and any contraindication to paclitaxel)
• Inflammatory bowel disease
• Known history of porphyria
• Any other condition which as per section 4.3 of the relevant SmPC or in the opinion of the investigator contraindicates the use of chemotherapy, radiotherapy and/or oral progestin tablets

Lab values

• Impaired renal function: ≤50ml/min (EDTA clearance, or measured creatinine clearance) or creatinine clearance ≤60 ml/min (calculated according to Cockcroft gault)
• History of active immune deficiency syndromes or uncontrolled HIV infection: HIV positive patients receiving effective antiretroviral therapy and CD4 count \>200 may be included

Other

• Peripheral neuropathy, ≥ grade 2

• Written informed consent and consent for data sharing for the overarching RAINBO programme
• 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, adapted from Vermij et al. 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 within 8 weeks of randomisation). Whole-body PET-CT scan is acceptable if this is part of standard of care at participating sites
• Age ≥ 18 years
• WHO performance status 0 or 1
• Expected start of adjuvant treatment within 10 weeks after surgery
• Patients must be accessible for treatment and follow-up
• Consent for the donation of a tissue block for translational research for the overarching RAINBO programme
• FIGO (2018) stage II EC with substantial LVSI or stage III NSMP tumours
• p53 wildtype, MMR proficient EC with no somatic pathogenic POLE variant (i.e. NSMP)
• ER+ by IHC (10% threshold applied) or Allred score of ≥3
• Absolute neutrophil count (ANC) ≥1.5 x 109 /l
• Platelets ≥ 100 x 109 /L
• Bilirubin ≤ 1.5 x UNL (or ≤ 3 x ULN for cases of known Gilbert's syndrome)
• AST/ALT ≤ 2.5 x UNL