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

PurposeVistusertib 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 (14)Carbon-isotope (C-14)-labelled vistusertib were characterised in this open-label phase I patient study.MethodsFour patients with advanced solid malignancies received a single oral solution dose of C-14-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(14)C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (T-max) <1.2h 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 (similar to 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 (AUC(0-))]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.ConclusionsThe 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.