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
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.
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.
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.
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.
KeywordsVistusertib AZD2014 ADME Solid malignancies Phase I Metabolism
The authors would like to thank the Experimental Cancer Medicine Team and Clinical Trials Unit at The Christie NHS Foundation Trust, Stephanie Gaynord (Quintiles, Reading, UK) for study oversight and coordination, Ruth Stow (Covance Metabolism Ltd, Harrogate, UK) for radioactivity measurements, Mark Savage (Unilab Bioanalytical Solutions, York, UK) for metabolite profiling and identification in the biological samples, and Angela Dymond (Covance, Leeds, UK) for the pharmacokinetic analysis.
This clinical study was sponsored and funded by AstraZeneca.
Compliance with ethical standards
Conflict of interest
All authors are current employees of AstraZeneca.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 8.Baselga J, Campone M, Piccart M, Burris H, Hope S, Rugo H (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:5209Google Scholar
- 10.Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W, Cavallin M, Bigley G, Womack C, Harrington E, Green S, Oelmann E, de Bono J, Ranson M, Banerji U (2014) First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res 21:3412–3419CrossRefGoogle Scholar
- 11.Powles T, Wheater M, Din O, Geldart T, Boleti E, Stockdale A, Sundar S, Robinson A, Ahmed I, Wimalasinghama A, Burke W, Sarker SJ, Hussain S, Ralph C (2016) Randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol 69:450–456CrossRefGoogle Scholar