In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma

Dewerth, Alexander; Wonner, Timo; Lieber, Justus; Ellerkamp, Verena; Warmann, Steven W.; Fuchs, Joerg; Armeanu–Ebinger, Sorin

doi:10.1007/s00383-012-3086-6

Cited by 6 publications

(1 citation statement)

References 46 publications

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“…However, a dose relationship was not clear; this is partly due to interpatient variability in pHH3 expression in some dose cohorts which precludes a conclusive observation. The decrease in the number of pHH3+ cells observed at the highest dose level of BI 831266 was consistent with selective Aurora kinase B inhibitory activity, which has been observed previously with other Aurora kinase B inhibitors in preclinical studies (data on file, Boehringer Ingelheim) [ 20 – 24 ]. We have therefore demonstrated the mechanism of action of BI 831266 in this trial.…”

Section: Discussionsupporting

confidence: 87%

A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors

et al. 2014

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SummaryPurpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4–130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48 %). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20 %), neutropenia, alopecia (16 % each), anemia, dry skin, and nausea (12 % each). Treatment-related grade ≥3 AEs were neutropenia (12 %), anemia (8 %), and febrile neutropenia (4 %); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4 %; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients’ solid tumors.

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Section: Discussionsupporting

confidence: 87%