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

作者：Foran James; Ravandi Farhad; Wierda William; Garcia Manero Guillermo; Verstovsek Srdan; Kadia Tapan; Burger Jan; Yule Murray; Langford Gillian; Lyons John; Ayrton John; Lock Victoria; Borthakur Gautham; Cortes Jorge; Kantarjian Hagop^*

来源：Clinical Lymphoma Myeloma & Leukemia, 2014, 14(3): 223-230.

DOI：10.1016/j.clml.2013.11.001

• Blood cancer
• Clinical
• Dose escalation
• Response
• Tolerability

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.

• 出版日期2014-6