A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

Abstract

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…A greater understanding of the development and progression of pediatric disease is crucial for optimizing study designs for control groups, stratification, and biomarker assay development. The observation that activity of an agent in pediatric leukemia may be limited to patients with specific mutations (38), or Rb status in solid tumors (16), would require recruitment of select patient populations.…”

“…Other toxicities were fatigue, infections, febrile neutropenia and increased alanine transaminase. The phase I/II trial of AT9283 for relapsed/refractory acute leukemia (NCT01431664) did not accomplish the primary endpoint of identifying a dose for phase II assessment (38). This study was terminated because there was no evidence of clinical efficacy for the doses examined.…”

The unpredictable Northern light: The rise and fall of the aurora kinase inhibitors?

“…The aim in the study reported by Vormoor et al. was to recruit 12–18 patients over three dose levels starting at a relatively low dose of 9 mg/m 2 /day, which is only approximately 10% of the maximum tolerated dose (MTD) in adult hematological malignancies (108 mg/m 2 /day, with cardiac safety signals at the MTD) . In the adult phase I study, some data were provided on phosphorylation of the aurora kinase B substrate phospho‐histone H3, which were however incomplete .…”

“…In addition, most patients are heavily pretreated by the time they are eligible for a phase I study, which may lead to organ toxicity and screen failures. This has clear logistical implications for the number of study center sites and countries that are needed to successfully complete such a trial: four centers in one country only – as attempted in the AT9283 study – do not longer suffice. For this reason, over the past decade, the Innovative Therapies for Children with Cancer consortium (http://www.itcc-consortium.org) developed a site network, now comprising 51 sites, with the aim to increase capacity (and quality) when it comes to delivering early phase studies in children with cancer.…”

“…If such data were available and validated, a biologically effective dose could have been developed rather than searching for an MTD. This is supported by the pharmacodynamic data in the pediatric leukemia study, which showed 87% inhibition of the target ex vivo at the highest dose level . The trial was run in parallel to a pediatric solid tumor study, which identified a pediatric MTD of 18.5 mg/m 2 /day, and inhibition of aurora kinase B by reduction in phospho‐histone H3 in 17/18 patients treated at a dose of 11.5 mg/m 2 /day or higher .…”