A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study.

Abstract

PURPOSE:

A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity.

EXPERIMENTAL DESIGN:

AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m(2)/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies.

RESULTS:

Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m(2)/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system-primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m(2)/d.

CONCLUSION:

AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined.

• Authors: Lucas Moreno, Lynley V Marshall, Andrew D J Pearson, Bruce Morland, Martin Elliott, Quentin Campbell-Hewson, Guy Makin, Sarah E R Halford, Gary Acton, Philip Ross, Shamim Kazmi-Stokes, Victoria Lock, Ana Rodriguez, John F Lyons, Alan V Boddy, Melanie J Griffin, Murray Yule, Darren Hargrave
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 2 Pg. 267-73 (Jan 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25370467 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

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

Topics

• Adolescent
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aurora Kinases (antagonists & inhibitors)
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Central Nervous System Neoplasms (drug therapy)
• Child
• Child, Preschool
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Neutropenia (chemically induced)
• Treatment Outcome
• Urea (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)