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.

• Authors: James Foran, Farhad Ravandi, William Wierda, Guillermo Garcia-Manero, Srdan Verstovsek, Tapan Kadia, Jan Burger, Murray Yule, Gillian Langford, John Lyons, John Ayrton, Victoria Lock, Gautham Borthakur, Jorge Cortes, Hagop Kantarjian
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 14 Issue 3 Pg. 223-30 (Jun 2014) ISSN: 2152-2669 [Electronic] United States
• PMID: 24355079 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
• Antineoplastic Agents
• Benzimidazoles
• Protein Kinase Inhibitors
• Urea

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzimidazoles (therapeutic use)
• Disease Progression
• Drug Administration Schedule
• Female
• Humans
• Leukemia (diagnosis, drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Primary Myelofibrosis (diagnosis, drug therapy, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Recurrence
• Treatment Outcome
• Urea (analogs & derivatives, therapeutic use)
• Young Adult