BACKGROUND: Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41). PRIMARY OBJECTIVE: To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. STUDY HYPOTHESIS: Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo. TRIAL DESIGN: This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse. PRIMARY ENDPOINT: The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. SAMPLE SIZE: A total of 220 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: NCT05611931.

Central and Eastern European Gynecologic Oncology Group Prague Czech Republic

Charles University and General University Hospital Prague Prague Czech Republic

Department of Clinical Therapeutics University of Athens School of Medicine Athens Greece

Department of Gynecology European Competence Center for Ovarian Cancer Charité Comprehensive Cancer Center Charité Berlin University of Medicine Berlin Germany

Department of Medicine and Surgery University of Milan Bicocca Milan Italy

Department of Obstetrics and Gynecology University of Cincinnati Cincinnati Ohio USA

Department of Oncology Rigshospitalet; Copenhagen University Hospital Copenhagen Denmark

Department of Oncology University of Turin Turin Italy

Florida Cancer Specialists and Research Institute West Palm Beach Florida USA

Frankston Hospital Frankston and Monash University Frankston Victoria Australia

Galway University Hospitals Galway Ireland

Grupo Espanol de Investigacion en Cancer Ginecologico Madrid Spain

Gynaecological Oncology KU Leuven University Hospitals Leuven Leuven Belgium

Gynecologic Oncology Group Foundation Philadelphia Pennsylvania USA

Gynecologic Oncology Group Foundation Prague Czech Republic

Gynecologic Oncology Mount Sinai Medical Center New York New York USA

Gynecologic Oncology Program European Institute of Oncology IRCCS Milan Italy

Karyopharm Therapeutics Inc Newton Massachusetts USA

Medical Oncology Hospital Clinico Universitario Valencia Spain

Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies Naples Italy

NYU Langone Health Perlmutter Cancer Center New York New York USA

Sheba Medical Center Tel Hashomer Israel

Stephenson Cancer Center University of Oklahoma Health Sciences Center Oklahoma City Oklahoma USA

Tel Aviv University Tel Aviv Israel

Texas Oncology Shenandoah Texas USA

University Hospitals Leuven Leuven Belgium

Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology Leuven Belgium

Women's Cancer Care Associates LLC Albany New York USA

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NCT05611931