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

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

Research output: Contribution to journalArticle

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/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 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.

Original languageEnglish (US)
Pages (from-to)223-230
Number of pages8
JournalClinical Lymphoma, Myeloma and Leukemia
Volume14
Issue number3
DOIs
StatePublished - Jun 2014
Externally publishedYes

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Aurora Kinases
Primary Myelofibrosis
Leukemia
Maximum Tolerated Dose
Aurora Kinase B
Leukemia, Myeloid, Accelerated Phase
Aurora Kinase A
Tumor Lysis Syndrome
1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
Mucositis
Leukopenia
Cardiomyopathies
Cytogenetics
Pneumonia
Therapeutics
Pharmacokinetics
Bone Marrow
Myocardial Infarction
Clinical Trials

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 14, No. 3, 06.2014, p. 223-230.

Research output: Contribution to journalArticle

Foran, J, Ravandi, F, Wierda, W, Garcia-Manero, G, Verstovsek, S, Kadia, T, Burger, J, Yule, M, Langford, G, Lyons, J, Ayrton, J, Lock, V, Borthakur, G, Cortes, J & Kantarjian, H 2014, 'A phase i and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis', Clinical Lymphoma, Myeloma and Leukemia, vol. 14, no. 3, pp. 223-230. https://doi.org/10.1016/j.clml.2013.11.001
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. / A phase i and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis. In: Clinical Lymphoma, Myeloma and Leukemia. 2014 ; Vol. 14, No. 3. pp. 223-230.
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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/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 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.",
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AU - Ravandi, Farhad

AU - Wierda, William

AU - Garcia-Manero, Guillermo

AU - Verstovsek, Srdan

AU - Kadia, Tapan

AU - Burger, Jan

AU - Yule, Murray

AU - Langford, Gillian

AU - Lyons, John

AU - Ayrton, John

AU - Lock, Victoria

AU - Borthakur, Gautham

AU - Cortes, Jorge

AU - Kantarjian, Hagop

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