Testing for Safety and Colorectal Cancer Preventive Effects of ONC201

PRIMARY OBJECTIVE: I. To evaluate the safety and toxicity of dordaviprone (ONC201) for the indication of cancer prevention in a healthy population of individuals who are at high risk (FAP and/or history of multiple adenomas \[excluding hereditary nonpolyposis colorectal cancer (HNPCC)\]) for recurrent colorectal adenomas. SECONDARY OBJECTIVES: I. To determine the dose(s) of ONC201 that yield(s) a statistically significant increase in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression. II. To determine the dose(s) of ONC201 that yield(s) a statistically significant increase in normal human mucosa TRAIL expression. EXPLORATORY OBJECTIVES: I. To evaluate the impact of ONC201 on: Ia. Cytokine/immune response profiles (with attention to interleukin \[IL\]-10, IL-17A, tumor necrosis factor \[TNF\]-alpha, IL-6, granzyme A, and perforin) in sera, normal colonic mucosa, and adenomas; Ib. Serum TRAIL concentration; Ic. Serum prolactin concentration; Id. Proliferation markers (Ki67), cell death markers (BCL2, Caspase 3), stemness markers (LGR5, CD44, CD133, ALDH), and natural killer (NK) cell infiltration in adenomas and in normal colonic mucosa; Ie. To evaluate for associations between observed toxicity and TRAIL expression; If. To establish organoids ex vivo and compare adenoma-derived organoid take rates between samples obtained prior to and following treatment. OUTLINE: This is a dose-escalation study. Patients receive ONC201 orally (PO) once weekly (QW) or once every 3 weeks (Q3W) for 13 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study. After completion of study treatment, patients are followed up at 21-35 days.