Abstract LB-018: ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies

Abstract

Abstract Background: ARQ 531 is a novel, ATP competitive reversible inhibitor Bruton's tyrosine kinase (BTK). BTK is a key regulator of the B cell receptor (BCR) signaling pathway that mediates signaling from the cell surface to the cytoplasm and into the nucleus. ARQ 531 is not metabolized by any of the major drug metabolizing CYP450 enzymes. Here we report pharmacokinetic profile of ARQ 531 in a phase I study evaluating safety, pharmacokinetics and pharmacodynamics activity and clinical activity of ARQ 531 in selected subjects with relapsed/refractory B-cell malignancies. Preclinical studies in rats, dogs and monkeys are also described. Methods: Oral and intravenous single dose pharmacokinetic studies of ARQ 531 were conducted in rats, dogs, and monkeys to determine oral bioavailability and drug exposure. In a standard ‘3+3' dose-escalation study design, ARQ 531 was given orally once per day beginning at 5 mg/dose and escalating for 4 weeks [NCT03162536]. Plasma samples were collected to determine ARQ 531 concentrations and whole blood / PBMCx to quantify pBTK inhibition. Plasma samples from each species were analyzed by liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS). Results: Consistent with preclinical studies, patients enrolled in the phase I study showed favorable exposures, the steady state peak to trough ratio was generally 3:1 or lower. ARQ 531 had an elimination half-life at steady state of ~24 hr and Cmax occurred 2 to 3 hours after dosing. Pharmacodynamic changes included suppression of BTK phosphorylation. No drug related AEs or DLTs have been observed thus far in the study. Conclusions: ARQ 531 demonstrates a favorable PK profile in humans supporting once daily dosing. Sufficient plasma levels are attained and high levels of pBTK inhibition in peripheral blood can be achieved following oral dosing. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented. Citation Format: Terence Hall, Yi Yu, Sudharshan Eathiraj, Deborah Stephens, Ian Flinn, Jennifer Woyach, Brian Schwartz, Ronald E. Savage. ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies [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 LB-018.