Phase I study of orally administered (14)carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies

Abstract

PURPOSE: Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. METHODS: Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. RESULTS: 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) <?1.2 h in all subjects). Overall, >?90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~?78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each <?10% area under the concentration-time curve from zero to infinity (AUC0-?)]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. CONCLUSIONS: The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.