Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy in preclinical cancer models via induction of the CHOP/DR5-mediated integrated stress response pathway and caspase-dependent apoptosis. In addition to cytotoxic effects in tumor cells, DRD2 antagonism can induce the activation of NK and other immune cells. The first-in-human trial of ONC201 previously established a recommended Phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a Phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics with weekly oral administration of ONC201. Methods: Patients ≥18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of ONC201 with weekly oral administration, which was subsequently confirmed in an 11-patient dose expansion cohort. Results: A total of 20 patients were enrolled: 3 at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. Pharmacokinetic profiles were consistent with every three week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 were detected, along with intratumoral induction of integrated stress response (CHOP/DR5), apoptosis (TUNEL) and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effector molecules was higher in patients who received ONC201 once every week versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in prolonged stable disease, intratumoral apoptotic signaling and enhanced immunostimulatory activity that warrants further investigation. Clinical trial information: NCT02250781; NCT02324621