NCIC CTG IND.181: Phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies
Purpose AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. Patients and methods Patients with advanced, incurable solid tumors or non-Hodgkin’s lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m2/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). Results 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m2/day (established as the maximum tolerated dose). The RP2D was 40 mg/m2/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). Conclusion In this study, AT9283 was well tolerated. The RP2D is 40 mg/m2/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.