A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora kinase inhibitor GSK1070916A.

Abstract

2525 Background: GSK1070916A is a potent and selective inhibitor of Aurora B and C. This phase I study in collaboration with GlaxoSmithKline was part of the Cancer Research UK Clinical Development Programme. Methods: Patients (pts) with advanced/metastatic solid cancers for whom there was no standard therapy, with adequate performance status and organ function were eligible for GSK1070916A (1 hour i.v. infusion days 1 – 5, every 21 days). The primary objectives were to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of GSK1070916A. The starting dose was 5mg/m2/day, with initial single pt cohorts, followed by “3 + 3” cohorts and expansion at the MTD. DLTs included prolonged (> 5 days) or complicated grade 4 neutropenia; the MTD was the highest dose at which < 1 of 3 - 6 pts experienced DLT. Cycle 1 blood and healthy skin biopsies were obtained for PK and PD assays. The expanded cohort included 6 pts having pre- and post-treatment functional imaging studies (FDG PET-CT and MRI), and a further 6 having paired tumour biopsies for PD studies. Results: Nine single pt cohorts received up to 73mg/m2/day of GSK1070916A with no grade 3 or 4 related adverse events. At 102.2mg/m2/day, 1 pt had a DLT (febrile neutropenia) and 2 pts non-DLT grade 4 neutropenia; this dose was considered unacceptably toxic and 23 pts received a lower dose of 85mg/m2/day; 7/23 pts had prolonged/complicated grade 4 neutropenia, 5 of whom continued GSK1070916A with dose reduction +/- delay. There were no treatment related deaths. A pt with ovarian cancer (102.2mg/m2/day) had a RECIST PR; 19 pts had stable disease for < 223 days. GSK1070916A PK were linear with a strong correlation between exposure (AUC) and reduction in neutrophils (r2 0.91). At the 85 mg/m2 dose, mean day 1 t1/2 was 8.98 hours and Cl 9.2 l/h; AUCinf was 10% higher on day 5 than day 1. PD results in healthy skin (phosphoHistone-H3, Ki 67 and cleaved caspase-3) were inconsistent. Conclusions: The MTD of GSK1070916A as a 1 hour i.v. infusion on days 1 – 5, every 21 days is 85mg/m2/day, with predictable and manageable neutropenia as the DLT and evidence of clinical activity. Serum levels of cytokeratin-18, tumour PD and functional imaging data will be presented. Clinical trial information: NCT01118611.

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

“…[NCT01118611]. The maximum tolerated dose was determined to be 85 mg/m 2 /day with neutropenia as the dose-limiting toxicity [ 94 ].…”

High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching

“…These Aurora kinase inhibitors were used in previous publications and the ability of the inhibitors to block downstream signaling is well validated 24 , 28 – 32 . Additionally, MK-5108, GSK1070916, and SNS-314 have already been used in one clinical trial each, indicating that safety profile for these inhibitors is already beginning to be established and providing strong rationale for selecting these inhibitors for use 29 , 33 , 34 . We considered the longest neurite the neurite most likely to become the axon, with the remaining neurites likely to become dendrites.…”

Purging human ovarian cortex of contaminating leukaemic cells by targeting the mitotic catastrophe signalling pathway

“…GSK1070916 exerts this effect by inhibiting AURKB/C and inhibits malignant cell proliferation in a wide range of tumour cell lines in vitro and in xenograft models of human tumours [ 35 ]. Aurora kinase inhibitors have not been approved for systemic cancer treatment in humans and only a Phase I clinical trial has been conducted with GSK1070916 [ 7 , 56 ]. Neutropenia caused by Aurora B toxicity was found to be the limiting factor in achieving an effective systemic treatment in a clinical setting [ 44 , 45 , 56 ].…”

“…Aurora kinase inhibitors have not been approved for systemic cancer treatment in humans and only a Phase I clinical trial has been conducted with GSK1070916 [ 7 , 56 ]. Neutropenia caused by Aurora B toxicity was found to be the limiting factor in achieving an effective systemic treatment in a clinical setting [ 44 , 45 , 56 ]. Obviously, this is of no concern to the current study in which ovarian cortex tissue is purged from malignant cells ex vivo, in the absence of perfusion.…”