Anticancer and immunostimulatory activity of the imipridone ONC201, a selective DRD2 antagonist, in advanced cancer patients

2586 Background: ONC201 is an orally active, small molecule selective antagonist of the G protein-coupled receptor DRD2 that has established a new class of compounds referred to as imipridones. A first-in-human trial of ONC201 defined its recommended phase II dose (RP2D) as 625mg using once every three week administration that was very well tolerated at doses that yielded antitumor effects. ONC201 also showed stimulatory effects on immune cells in preclinical studies, including increased intratumoral NK cell infiltration in xenografts. Based on the exceptional safety profile of ONC201, weekly dosing has been evaluated. Methods: This open-label, 3+3 dose-escalation study used a starting dose of 375mg and escalated to 625mg using a weekly administration schedule. The primary endpoint was to determine the RP2D of ONC201 and secondary endpoints included PD, PK, toxicity, and anti-tumor efficacy. Based on signs of clinical activity and preclinical tumor type sensitivity studies of ONC201, the patient population was enriched for advanced glioblastoma, prostate cancer, and endometrial cancer. Six additional patients were treated at the weekly RP2D. Results: The RP2D for the weekly regimen was defined as 625 mg. Twelve evaluable patients were treated at this dose level and no drug-related AEs > grade 1 occurred. Five patients had stable disease by RECIST criteria for 21-29 weeks. A metastatic prostate cancer who received 375mg ONC201 weekly had significantly diminished intensity in bone scans after 6 doses. PK was consistent with previous reports: Cmax consistently reaches therapeutic micromolar plasma concentrations, ~11 hour half-life, evidence of sustained and delayed activity, no systemic accumulation. In agreement with preclinical observations of ONC201-induced NK cell populations, a 2-10 fold increase in circulating activated NK cells was observed in 5 prostate cancer patients. Conclusions: ONC201 is well tolerated at an oral dose of 625mg weekly, exhibits sustained and late anti-cancer activity, and increases circulating NK cells. Observation in this study, and other clinical studies, warrant further evaluation of the immune oncology effects of ONC201. Clinical trial information: NCT02250781.