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Clin Cancer Res. 2017 Aug 1;23(15):4163-4169. doi: 10.1158/1078-0432.CCR-16-2658. Epub 2017 Mar 22.

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

Author information

1
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. steinmn@cinj.rutgers.edu.
2
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
3
Formerly at Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
4
Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
5
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
6
Oncoceutics, Philadelphia, Pennsylvania.

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 Cmax 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.

PMID:
28331050
DOI:
10.1158/1078-0432.CCR-16-2658
[Indexed for MEDLINE]
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