ONC201 for chemoprevention of colorectal cancer.

TPS246 Background: Dordaviprone (ONC201) is an oral small molecule that antagonizes dopamine receptor D2/3 and agonizes the mitochondrial protease ClpP, leading to activation of the integrated stress response and induction of TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. In preclinical murine models, ONC201 reduces the burden of colorectal adenomas and modulates inflammatory cytokine signaling, supporting its development as a chemopreventive agent in populations at risk for colorectal cancer (CRC). Despite endoscopic surveillance and non-invasive screening, individuals with familial adenomatous polyposis (FAP) or a history of multiple adenomas remain at elevated risk for CRC, underscoring the need for safe, mechanism-driven preventive strategies. Methods: This first-in-human, multi-center, open-label Phase I prevention study evaluates the safety and tolerability of ONC201 in individuals with FAP or multiple colorectal adenomas of unknown genetic etiology. Eligible participants include adults (≥18 years) at high risk for recurrent colorectal adenomas, defined as either a diagnosis of FAP or findings of >5 small adenomas (