A Phase I and Pharmacodynamic Study of AT9283, a Small-Molecule Inhibitor of Aurora Kinases in Patients With Relapsed/Refractory Leukemia or Myelofibrosis

Aurora kinase (AK) inhibitors are active in a variety of leukemic models. A dose-escalation study of AK inhibitor AT9283 was performed in patients with relapsed or refractory leukemias. Dose-limiting toxicities included multiorgan failure, hypertension, and myocardial infarction. The maximum tolerated dose was identified as 324 mg/m(2)/72 h. Approximately one-third of patients with acute myeloid leukemia experienced significant reduction in bone marrow blasts; no durable responses were seen. 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/m2/72 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 1 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. (C) 2014 Elsevier Inc. All rights reserved.