First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Abstract

Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a C_max of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163-9. ©2017 AACR.

Figure 1. ONC201 plasma concentrations following the first dose of ONC201

Concentrations are shown as (A) the mean for each dose cohort in dose escalation, or (B) for all individuals treated at 625 mg. Data points below the limit of detection (1ng/mL) are excluded from the plots. Error bars indicate standard deviation.

Figure 2. Pharmacodynamic assays for apoptosis and DRD2 antagonism

(A) M30 assay ratio in dose escalation patients who experienced induction over baseline (n=2 per sample). (B) Maximum versus baseline serum prolactin levels in dose-escalation cohort of patients.

Figure 3. Antitumor activity in metastatic lesions

(A) Waterfall analysis on a lesion-by-lesion basis. Best change in lesion size is defined as the maximal reduction or minimal increase in sum of longest dimensions of target lesions relative to pretreatment assessment. 25/28 patients had measurable tumors at baseline and at least one post-treatment evaluation. Letters above or below bar denotes location of the lesion: V = liver; L = lung; N = lymph node; A = adrenal gland; P = primary tumor; B = bone. (B) Metastatic lung lesion of an endometrial cancer patient at baseline and after 8 doses of 625mg ONC201.