A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.

ABSTRACT

BACKGROUND: This study sought to identify the maximum tolerated dose (MTD) of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics, and preliminary evidence of efficacy. PATIENTS AND METHODS: AT9283 was administered as a continuous 72-hour infusion every 21 days. Doses were escalated by a standard 3 + 3 design. After the MTD for the 72-hour infusion was identified, infusion duration was increased incrementally to 96 hours and 120 hours. In total, 48 patients received ≥ 1 cycle of AT9283. Median age was 61 years (range, 22-86 years); 56% were men; 75% were diagnosed with AML; and 89% had received ≥ 3 (up to 16) prior lines of therapy. RESULTS: 324 mg/m(2)/72 h AT9283 was determined to be the MTD. Dose-limiting toxicities (DLTs) were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leukopenia and mucositis. Bone marrow blasts decreased ≥ 38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of Aurora kinase B inhibition. Two patients with accelerated-phase chronic myeloid leukemia showed evidence of benefit, manifested as a cytogenetic response in 1 case; 1 patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. CONCLUSION: AT9283 tolerability was strongly dose-dependent, with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations.