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 (<1 cm) or ≥3 adenomas with at least one ≥10 mm on colonoscopy within the past 5 years, excluding those with a history of Lynch syndrome (HNPCC). Participants with ≥2 adenomas ≥5 mm identified during standard-of-care colonoscopy will undergo baseline tissue (adenoma and normal mucosa) sampling, with at least one polyp intentionally retained and accessible by flexible sigmoidoscopy for post-treatment sampling. Subsequently, participants will be assigned to an ONC201 dose level (120 mg, 375 mg, 500 mg) and frequency (weekly versus every 3 weeks) using a “Rolling Six” rule-based design, based on tolerability. Each dose cohort will be comprised of at least 5 participants, with a maximum of 6 participants, who will receive oral ONC201 for approximately 12 weeks. At the end of treatment, participants will undergo flexible sigmoidoscopy (or colonoscopy if clinically indicated), during which time the remaining polyp(s) and additional biopsies of normal colorectal tissue will be collected. The primary endpoint is the proportion of participants with unacceptable toxicity to ONC201. Secondary endpoints are to evaluate the mean changes in TRAIL expression in adenomas and normal mucosa. Exploratory endpoints include serum cytokine and immune profile changes and tissue-based markers of proliferation, apoptosis, stemness, and NK-cell infiltration. Enrollment is ongoing across U.S. academic centers, including Brown University, University of Michigan, Cleveland Clinic Foundation, Ohio State University, and Washington University in St. Louis. Funding is provided by NCI/Division of Cancer Prevention. Clinical trial information: NCT05630794 .