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First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor, AZD2014.
Dean E, Basu B, Puglisi M, Greystroke A, Ong M, Burke WM, Cavallin M, Bigley G, Womack C, Harrington EA, Green S, Oelmann E, de Bono JS, Ranson MR, Banerji U
Clinical Cancer Research. 2015;.
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Abstract
PURPOSE: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor which has shown in-vitro and in-vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN: A rolling six dose escalation was performed to define a maximal tolerated dose (MTD) (Part A) and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and post-treatment biopsies (Part B). AZD2014 was administered orally twice a day (BD) continuously. Flow cytometry, ELISA and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry. RESULTS: A total of 56 patients were treated across a dose range of 25 -100 mg. The MTD was 50 mg BD. The dose limiting toxicities were fatigue and mucositis. At the MTD the most common AEs were fatigue (78%), nausea (51%) and mucositis (49%) but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUCss 6686 ng.hr/mL, Cmaxss 1664 ng/mL) were consistent with activity in pre-clinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8/8 and 5/9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer who were found to have a PDGFR and ERBB2 mutation, respectively. CONCLUSIONS: The recommended phase II dose for further evaluation of AZD2014 is 50 mg BD and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor and clinical responses.