Atezolizumab Trial in Endometrial Cancer - AtTEnd

Inclusion Criteria: I-1. Newly diagnosed, histologically-confirmed with residual disease after surgery eithermeasurable or evaluable, or inoperable stage III-IV endometrial carcinoma/carcinosarcoma,after diagnostic biopsy, and naïve to first line systemic anti-cancer treatment. Recurrentendometrial cancer patients if not yet treated for recurrent disease. I-2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 I-3. Age ≥ 18 yearsI-4. Only one prior line of systemic platinum-based regimen is permitted if theplatinum-free interval ≥ 6 months. Such prior line is the up-front/adjuvant treatment whichcan be concurrent chemoradiation or concurrent chemoradiation followed by chemotherapy oronly chemotherapy. I-5. Patients with history of primary breast cancer may be eligible provided they completedtheir definitive anticancer treatment more than 3 years ago and they remain breast cancerdisease free prior to start of study treatment. I-6. Previous pelvic and outside pelvis radiation is allowed if completed more than 6 weeksago. I-7. Signed informed consent and ability to comply with treatment and follow-up. I-8. Representative FFPE tumor sample or, only if unfeasible, at least 20 unstained slidesfrom initial surgery or from diagnostic biopsy, in case surgery was not performed,available and sent to central laboratory for Micro Satellite (MS) determination prior torandomization. I-9. Patients must have normal organ and bone marrow function :

1. Haemoglobin ≥ 10.0 g/dL.
2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
3. Platelet count ≥ 100 x 109/L.
4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
5. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) andAlanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 xULN, unless liver metastases are present in which case they must be ≤ 5 x ULN.
6. Serum creatinine ≤ 1.5 x institutional ULN

Exclusion Criteria: E-1. Other malignancy within the last 5 years except: adequately treated non-melanoma skincancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) ofthe breast. Patients with a history of localized malignancy diagnosed over 5 years ago maybe eligible provided they completed their adjuvant systemic therapy prior to randomizationand that the patient remains free of recurrent or metastatic disease. E-2. Patients with uterine leiomyosarcoma . E-3. Major surgery within 4 weeks of startingstudy treatment or patients who have not completely recovered from the effects of any majorsurgery. E-4. Previous allogeneic bone marrow transplant or previous solid organ transplantation. E-5. Administration of other simultaneous chemotherapy drugs, any other anticancer therapyor anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trialtreatment period (hormonal replacement therapy is permitted). E-6. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1,or anti-PDL1 therapeutic antibodies or anti-CTLA4 . E-7. Treatment with systemic immunostimulatory agents (including but not limited tointerferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of thedrug (whichever is shorter) prior to Cycle 1, Day 1. E-8. Treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone, cyclophosphamide,azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents)within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemicimmunosuppressive medications during the trial. However, please note that the use ofinhaled corticosteroids for chronic obstructive pulmonary disease or for asthma is allowed,as well as the use of mineralocorticoids (e.g., fludrocortisones) and low-dose supplementalcorticosteroids for adrenocortical insufficiency and for patients with orthostatichypotension. The use of corticosteroids as premedication for paclitaxel-based regimen isallowed). E-9. History of autoimmune disease, including but not limited to myasthenia gravis,myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,vasculitis, or glomerulonephritis [please note: patients with a history of autoimmunehypothyroidism on a stable dose of thyroid replacement hormone are eligible; patients withcontrolled Type 1 diabetes mellitus on a stable insulin regimen are eligible; history ofidiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizingpneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia) is permitted]. E-10. Immunocompromised patients, e.g., patients who are known to be serologically positivefor human immunodeficiency virus (HIV). E-11. Patients with active hepatitis B (defined as having a positive hepatitis B surfaceantigen [HBsAg] test at screening) or hepatitis C .

1. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive total hepatitis B coreantibody [HBcAb]) are eligible only if hepatitis B virus (HBV) DNA is negative. TheHBV DNA test will be performed only for patients who have a positive total HBcAb test.
2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerasechain reaction (PCR) is negative for HCV RNA. The HCV RNA test will be performed onlyfor patients who have a positive HCV antibody test. E-12. Active tuberculosis (all patients will have tuberculin [PPD] skin test orInterferon-Gamma Releasing Assay [IGRA] done locally prior to inclusion to study) E-13.Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 E-14. Administrationof a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation thatsuch a live attenuated vaccine will be required during the study. Influenza vaccinationshould be given during influenza season only (example approximately October to March in theNorthern Hemisphere). Patients must not receive live, attenuated influenza vaccine. E-15. Clinically significant (e.g. active) cardiovascular disease, including:
3. Myocardial infarction or unstable angina within ≤ 6 months of randomization,
4. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),
5. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlledatrial fibrillation are eligible),
6. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering withactivities of daily living [ADL] requiring repair or revision) E-16. Resting ECG withQTc > 470 msec on 2 or more time points within a 24 hour period or family history oflong QT syndrome. E-17. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRIof the brain is mandatory (within 4 weeks prior to randomization) in case of suspectedbrain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in anycase of suspected central nervous system (CNS) involvement . E-18. History or evidence upon neurological examination of central nervous system (CNS)disease, unless asymptomatic and adequately treated with standard medical therapy. E-19. Evidence of any other disease, metabolic dysfunction, physical examination finding orlaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or puts the patient at high risk fortreatment related complications. E-20. Women of childbearing potential (<2 years after last menstruation) not willing to usehighly-effective means of contraception. E-21. Pregnant or lactating women. E-22. History of severe allergic, anaphylactic, or otherhypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. E-23. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamsterovary cells or to any component of the atezolizumab formulation. E-24. Known hypersensitivity reaction or allergy to drugs chemically related tocarboplatin, paclitaxel, or their excipients that contraindicates the subject'sparticipation