Abstract 4479: ONC201 is non-toxic at efficacious doses in vitro and in vivo

Abstract

Abstract ONC201 is a small molecule that is entering clinical trials based on its favorable preclinical profile that includes robust anti-tumor activity in several preclinical models of advanced cancers. Despite inducing a strong cytotoxic response in tumor cells, ONC201 does not induce cell death in normal cells under the same conditions. In addition to a lack of cytoxicity towards normal cells, ONC201 also does not appear to be genotoxic based on gamma-H2AX assessment. Recent mechanistic studies have implicated the early stage induction of the ER stress response by ONC201, which includes induction of DR5 as part of its pro-apoptotic response. Biochemical studies reveal that ONC201 does not induce DR5 in normal cells at doses that cause strong DR5 induction in tumor cells. In accordance with in vitro profile, efficacious ONC201 dose schedules in murine models are also well tolerated without apparent alterations of normal tissue histology or significant loss of body weight. Similar observations were revealed in GLP toxicology studies in beagle dogs and Sprague-Dawley rats. Dogs received a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 3.57 g, respectively. Rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 2.25 g, respectively. There were no deaths or dose-limiting toxicities. The only findings that were observed in both rats and dogs occurred at the highest doses tested and were mild and reversible: decreased activity (no indications of anemia), decreased food consumption (weight loss only seen in rats), and salivation. The NOAEL was at least 42 mg/kg in dogs and at least 125 mg/kg in rats. In summary, these in vitro and in vivo studies support that ONC201 has a large and favorable therapeutic index that is compelling given its powerful single agent anti-tumor efficacy. The coupling of the strong efficacy and safety profile of ONC201 is unique among cancer therapies and opens a broad range of clinical applications for its future development, including potential for combinatorial therapeutics. Citation Format: Joshua E. Allen, Wafik S. El-Deiry. ONC201 is non-toxic at efficacious doses in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4479. doi:10.1158/1538-7445.AM2015-4479