Refining Adjuvant Treatment in Endometrial Cancer Based on Molecular Features

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 followinghistotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma,uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrialcarcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of theaforementioned histotypes.

• Full molecular classification performed following the diagnostic algorithm describedin WHO 2020 (5th Edition, IARC, Lyon, 2020)

• Hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy orsentinel node biopsy, without macroscopic residual disease after surgery

• No distant metastases as determined by pre-surgical or post-surgical imaging (CTscan 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, permissionfor the contribution of a tissue block for translation research and permission forthe use and sharing of data for the overarching research project according to thelocal Ethics Committee requirements.

Exclusion Criteria overarching RAINBO program:

• History of another primary malignancy, except for non-melanoma skin cancer, in thepast 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) >40mL/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 ofcreatinine 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 unconjugatedin the absence of hemolysis or hepatic pathology), who will be allowed only inconsultation 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 tothe first dose of the IP

• History of allogenic organ transplantation

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten 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 withfeatures suggestive of MDS/AML

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)

• Active infection, including: tuberculosis (clinical evaluation that includesclinical history, physical examination and radiographic findings, and TB testing inline with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2antibodies). Patients with a past or resolved HBV infection (defined as the presenceof hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction 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 requiredwashout 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) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents.

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.

• Medical or psychological condition which in the opinion of the investigator wouldnot permit the patient to complete the study or sign meaningful informed consent.

The MMRd-GREEN trial

Inclusion criteria:

• Mismatch repair deficient EC

• Histologically confirmed (FIGO 2009) stage IB/II EC with myometrial or cervicalstroma involvement and lympovascular space invasion (LVSI) OR Stage III EC OR StageIVA 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) >40mL/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 ofcreatinine 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 unconjugatedin the absence of hemolysis or hepatic pathology), who will be allowed only inconsultation with their physician.>> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 xULN

Exclusion criteria:

• Pathogenic POLE mutation(s)

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of investigational medicinal product (IMP)

• History of allogenic organ transplantation

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten 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 ofdurvalumab. Note: Patients, if enrolled, should not receive live vaccine whilstreceiving IP and up to 30 days after the last dose of IMP.

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab with the exceptions of:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection).

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent.

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication).

• History of active primary immunodeficiency

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome. The following are exceptions to this criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal 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 hepatitisB core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive forhepatitis C (HCV) antibody are eligible only if polymerase chain reaction isnegative for HCV RNA.

• Medical or psychological condition which in the opinion of the investigator wouldnot 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 FIGOstage, 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 ofFIGO stage, grade, and LVSI:

• stage IA (not confined to polyp), grade 3 - Stage III not included in maincohort

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

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient must sign a consent form prior toenrolment in the trial to document their willingness to participate. A similarprocess must be followed for sites outside of Canada as per their respectivecooperative group's procedures.

• Patient is able (i.e., sufficiently fluent) and willing to complete the QOL and/orhealth utility questionnaires in either English, French or a validated language. Thebaseline assessment must be completed within the required timelines, prior toenrolment. Inability (lack of comprehension in English or French, or otherequivalent reason such as cognitive issues or lack of competency) to complete thequestionnaires will not make the patient ineligible for the study. However, abilitybut unwillingness to complete the questionnaires will make the patient ineligible.

• Patients must be accessible for treatment and follow up. Patients enrolled on thistrial must be treated and followed at the participating center. Investigators mustassure themselves the patients enrolled on this trial will be available for completedocumentation of the treatment, adverse events, and follow-up.

• Patients must agree to return to their primary care facility for any adverse eventswhich may occur through the course of the trial.

• In accordance with CCTG policy, protocol treatment is to begin within 10 weeks ofhysterectomy/bilateral salpingo-oophorectomy.

Exclusion criteria:

• Prior chemotherapy for EC

• Isolated tumor cells identified in lymph node(s) for main study cohort (patient canbe included in exploratory cohort)