Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration

Abstract

Background ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. 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 (PD) of weekly 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 weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results Twenty patients were enrolled: three 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. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly 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 enhanced immunostimulatory activity that warrants further investigation. Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors). Electronic supplementary material The online version of this article (10.1186/s40425-019-0599-8) contains supplementary material, which is available to authorized users.

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

“…Subsequently, in vivo studies in xenograft tumor models demonstrated improvement in antitumor efficacy including suppression of metastasis with once weekly administration relative to every three-week dosing [40] . Additionally, enhanced immune stimulatory activity was observed with weekly dosing relative to every three-week dosing [99] . Considering these observations, its benign safety profile, and wide therapeutic index, ONC201 was subsequently administered once weekly in clinical trials.…”

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

“…Given that ONC201 has anti-tumor e cacy in preclinical models, the safety/tolerability and e cacy of ONC201 has been and is being tested in phase I and phase II clinical trials, respectively. Oral weekly ONC201 is well tolerated with very few adverse events and results in clinical activity in advanced solid tumors, including ECs (23,(53)(54)(55). The unique features of ONC201 to occupy DRD2 and DRD3 at physiological concentrations strengthens the excellent safety pro le of ONC201 in clinical trials (53).…”

“…Oral weekly ONC201 is well tolerated with very few adverse events and results in clinical activity in advanced solid tumors, including ECs (23,(53)(54)(55). The unique features of ONC201 to occupy DRD2 and DRD3 at physiological concentrations strengthens the excellent safety pro le of ONC201 in clinical trials (53). Importantly, multiple ongoing phase I/II trials of ONC201 as a signal agent or in combination with other agents in solid tumors and hematologic malignancies has been initiated in the US.…”

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

“…Recent preclinical and clinical data have hinted at an efficacy of ONC201 in several solid cancers including GBM [21][22][23]25,27 . Originally identified as an inducer of TRAIL, ONC201 inhibits D2-like dopamine receptors DRD2 and DRD3 and activates the mitochondrial protease ClpP, a key player in the mitochondrial unfolded protein response 52,53 .…”

“…This results in dual inactivation of Akt/ERK signaling that drives Foxo3a-mediated TRAIL gene induction to promote pro-apoptotic and anti-proliferative effects in tumor cells, but not in normal cells [16][17][18][19][20] . With p53-independency, low toxicity and excellent penetration of the BBB, ONC201 is currently being evaluated in multiple clinical trials for select advanced malignancies, including myeloma, leukemia, lymphoma, endometrial cancer, high grade glioma, and other solid tumors [21][22][23][24][25][26][27][28] .…”