Background: ONC201 is an orally active, first-in-class small molecule activator of the integrated stress response that selectively upregulates ATF4 to trigger tumor cell death. Preclinical studies have established the compelling antitumor efficacy of the small molecule in a range of advanced solid tumors as well as its excellent safety profile in animals. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D) in patients with advanced solid tumors. Methods: This open-label study treated 10 patients during the single-patient cohort dose escalation portion of the trial. The human starting dose was 125mg, which represents 1/10^th of the no-adverse-adverse-effect-level in animal toxicology studies using standard allometric conversion. Results: The RP2D was defined as 625 mg and no Grade > 1 drug-related adverse events occurred on this trial, which enrolled patients at increasing dose levels of 125mg, 250mg, 375mg, 500mg, and finally 625mg. Pharmacokinetic analysis revealed saturation of absorption at 375mg, suggesting dose escalation above 625mg was not warranted. The terminal half-life was 9.6 hours, C_max values ranged from 1.5 - 7.5 ug/mL (~3.9-19.4 uM), and the AUC was 25 hr ug/L. Prolonged induction of caspase-cleaved keratin 18 and induction of TRAIL was observed in serum samples. Eight of 10 patients had stable disease and one patient with endometrial cancer underwent a mixed response. 17 of 25 additional patients have been accrued in an ongoing expansion phase. The available results from the expansion cohort confirm the excellent safety, and the pharmacokinetic and pharmacodynamic profiles of ONC201 at the recommended phase II dose of 625mg every three weeks. Conclusions: This study demonstrates that ONC201 is well tolerated and active at an oral dose of 625mg, warranting further evaluation in lead indications. Clinical trial information: NCT02250781.