Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1307-1313 |
Number of pages | 7 |
Journal | Annals of Oncology |
Volume | 23 |
Issue number | 5 |
DOIs | |
State | Published - May 1 2012 |
Externally published | Yes |
Keywords
- Advanced solid malignancies
- AT9283
- Aurora kinase inhibitor
- Phase I
ASJC Scopus subject areas
- Hematology
- Oncology