Abstract 4529: Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update

Abstract

Abstract Background LOXO-101 is the first highly selective and potent small-molecule inhibitor of TRKA, TRKB, and TRKC to be dosed clinically. It has approximately 100-fold selectivity over other kinase and non-kinase targets. We report here the interim results of the first-in-man Phase I study which evaluates the safety, maximum-tolerated dose (MTD), and PK of LOXO-101 in patients with advanced solid tumors. Methods This is an ongoing open-label, multicenter, 3+3 dose escalation Phase I study of LOXO-101. Patients with solid tumors refractory to standard therapy, with normal hematopoietic and major organ function were eligible for study. LOXO-101 was administered orally as a single dose, followed by QD or BID doses for continuous 28-day cycles. Receptor occupancy was determined with an Emax model based on unbound LOXO-101 plasma concentrations. Results To date, data are available for 8 patients including patients treated at each of the first two dose levels, 50 mg QD and 100 mg QD. LOXO-101 has been well tolerated; the MTD has not been reached and no adverse events have been reported more than once other than fatigue (two patients; related but not serious) and syncope (two patients; unrelated and serious). Maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing and exposure increased in approximate proportion with dose. Mean values of Cl/F, V/F, and half-life were 0.5 L/h/kg, 2 L/kg, and 3.5 h, respectively, and were independent of dose. Exposure was similar following the single dose and on Day 1 and Day 8 of repeated dosing in all subjects. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations with once-daily dosing of 50 or 100 mg. Conclusions LOXO-101 has been well tolerated and has sufficient systemic exposure for robust inhibition of the TRKA, TRKB, and TRKC kinases without inhibition of other kinases. With dose escalation continuing, additional data and follow up will be provided at time of presentation. Citation Format: Howard A. Burris, Alice T. Shaw, Todd M. Bauer, Anna F. Farago, Robert C. Doebele, Steven Smith, Nisha Nanda, Scott Cruickshank, Jennifer A. Low, Marcia S. Brose. Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update. [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 4529. doi:10.1158/1538-7445.AM2015-4529