BACKGROUND: AT9283 is an inhibitor of aurora kinases A and B with antitumor activity in preclinical models. This a First in Human phase I study assessed the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of AT9283. PATIENTS AND METHODS: Patients with advanced tumors received AT9283 as a continuous central venous infusion over 3 days in cohorts of three to six patients starting at 1.5 mg/m(2)/day (equivalent to 4.5 mg/m(2)/72 h). The oral bioavailability of AT9283 was assessed in a cohort of seven patients. Pharmacodynamic analysis of biomarkers included phosphorylation of histone H3 on serine 10, proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma. RESULTS: Forty patients were included in all analyses. AT9283 was generally well tolerated with main toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue and alopecia. The dose-limiting toxicity of AT9283 was grade 3 febrile neutropenia in two patients at 36 mg/m(2)/72 h and the maximum tolerated dose (MTD) was established at 27 mg/m(2)/72 h. Systemic exposure was dose proportional. The mean oral bioavailability of a 0.9 mg/m(2) dose was 29.4% (range 11.2%-36.7%). Pharmacodynamic analyses indicated antiproliferative and apoptotic activity of AT9283. Four patients with esophageal, non-small-cell lung cancer (n = 2) and colorectal cancer demonstrated RECIST stable disease ≥ 6 months. CONCLUSION: AT9283 was well tolerated up to the MTD of 27 mg/m(2)/72 h. AT9283 is currently assessed in phase II trials.
BACKGROUND:AT9283 is an inhibitor of aurora kinases A and B with antitumor activity in preclinical models. This a First in Human phase I study assessed the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of AT9283. PATIENTS AND METHODS: Patients with advanced tumors received AT9283 as a continuous central venous infusion over 3 days in cohorts of three to six patients starting at 1.5 mg/m(2)/day (equivalent to 4.5 mg/m(2)/72 h). The oral bioavailability of AT9283 was assessed in a cohort of seven patients. Pharmacodynamic analysis of biomarkers included phosphorylation of histone H3 on serine 10, proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma. RESULTS: Forty patients were included in all analyses. AT9283 was generally well tolerated with main toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue and alopecia. The dose-limiting toxicity of AT9283 was grade 3 febrile neutropenia in two patients at 36 mg/m(2)/72 h and the maximum tolerated dose (MTD) was established at 27 mg/m(2)/72 h. Systemic exposure was dose proportional. The mean oral bioavailability of a 0.9 mg/m(2) dose was 29.4% (range 11.2%-36.7%). Pharmacodynamic analyses indicated antiproliferative and apoptotic activity of AT9283. Four patients with esophageal, non-small-cell lung cancer (n = 2) and colorectal cancer demonstrated RECIST stable disease ≥ 6 months. CONCLUSION:AT9283 was well tolerated up to the MTD of 27 mg/m(2)/72 h. AT9283 is currently assessed in phase II trials.
Authors: S F Dent; K A Gelmon; K N Chi; D J Jonker; N Wainman; C A Capier; E X Chen; J F Lyons; L Seymour Journal: Invest New Drugs Date: 2013-09-27 Impact factor: 3.850
Authors: Janna K Duong; Melanie J Griffin; Darren Hargrave; Josef Vormoor; David Edwards; Alan V Boddy Journal: Br J Clin Pharmacol Date: 2017-03-05 Impact factor: 4.335
Authors: Christian Dittrich; Michael A Fridrik; Robert Koenigsberg; Chooi Lee; Rainer-Georg Goeldner; James Hilbert; Richard Greil Journal: Invest New Drugs Date: 2014-12-23 Impact factor: 3.850