Abstract 5568: Clinical immunostimulatory activity of imipridone ONC201, a selective DRD2 antagonist, in advanced solid tumor patients
Authors: Tarapore Rohinton S. , Stein Mark N. , Zloza Andrew , Rodriguez Lorna , Newman Jenna , Cheeson Charles , Stogniew Martin , Oster Wolfgang , Allen Joshua E. 
Published: August 2018

Abstract
Background: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor that is overexpressed in several malignancies and is also expressed in a variety of immune cells including Natural Killer (NK) cells. Interestingly, pharmacological antagonism of DRD2 results in induction of apoptosis in tumor cells and proliferation of immune cells. ONC201 is an anti-cancer, small molecule DRD2 antagonist that is in clinical trials for various cancers that overexpress DRD2 following completion of the first-in-human trial that established its recommended phase II dose of 625mg.
Methods: A Phase I trial previously investigated single agent oral ONC201 in adult advanced solid tumor patients on a once every one (Q1W) or three weeks (Q3W) administration schedule. Twenty-eight evaluable patients received ONC201 on a Q3W schedule while 20 evaluable patients received ONC201 on a Q1W schedule. Levels of serum immune cytokines and effector molecules were evaluated throughout treatment using the Legendplex Assay. Peripheral blood mononuclear cells (PBMCs) and tumor biopsies from patients were also probed for immunomodulatory effects following treatment initiation.
Results: Early serum immune cytokine induction occurred in the majority of patients on the trial, whereas delayed induction of immune effectors was exclusive to patients who experienced at least stable disease by RECIST criteria. Analysis of PBMCs revealed an increase in the number of circulating NK cells, as well as their expression of granzyme B, which occurs with NK cell activation, up to 3 days after initiating ONC201. Intratumoral infiltration of granzyme B+ NK cells was evident in one patient who underwent an on-treatment biopsy 10 days after beginning ONC201. A statistically significant increase in the induction of immune cytokines and effectors was apparent in patients who received ONC201 once every week versus once every three weeks.
PK analyses in patients dosed on a Q1W schedule revealed therapeutic Cmax, AUC, and half-life values that were consistent with that of Q3W dosing and similar between the first (cycle 1) and fourth (cycle 2) dose. Prolonged stable disease for &gt;6 months was observed in several prostate and endometrial cancer patients. Patients who had stable disease for &gt;12 weeks had a significantly higher induction of cytokines and effector molecules compared to patients that progressed rapidly.
Conclusions: ONC201 exhibits immunostimulatory activity in advanced cancer patients that is well tolerated and may be associated with clinical benefit. Activation of immune cells by ONC201 is another dimension of its efficacy that should accounted for when considering its clinical evaluation as a single agent or in combination for the treatment of advanced cancers.
Citation Format: Rohinton S. Tarapore, Mark N. Stein, Andrew Zloza, Lorna Rodriguez, Jenna Newman, Charles Cheeson, Martin Stogniew, Wolfgang Oster, Joshua E. Allen. Clinical immunostimulatory activity of imipridone ONC201, a selective DRD2 antagonist, in advanced solid tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5568.