A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered every three weeks in patients with advanced solid tumors.

Abstract

3011 Background: The serine/threonine kinase Aurora B regulates several mitotic processes and is an attractive target for therapeutic intervention. BI 811283 has demonstrated potent antitumor activity in cancer models at well-tolerated doses, with hallmarks of Aurora B inhibition. Methods: Patients with advanced, nonresectable and/or metastatic solid tumors were randomized to two treatment schedules (q2w and q3w) in a bicentric phase I dose-escalation study. The primary outcome measure was to determine the MTD of each treatment schedule—results for the q2w schedule are reported separately. In the 3-week treatment schedule (q3w), patients received BI 811283 as a 24 h i.v. infusion on day 1 of each 21-day treatment cycle. To determine the MTD, a modified 3+3 trial design with de-escalation when DLT was reached was conducted. After determination of the MTD, up to nine additional patients could be treated. PK and determinations of the phosphorylation of histone H3 in skin biopsies as PD assessments were performed. Results: Until December 2009, 57 patients had been treated with 13.5-300 mg. After reaching DLT and de-escalation, the MTD was determined as 230 mg. Reversible hematotoxicity was the main AEs at the highest dose levels dose-limiting toxicities were neutropenia and febrile neutropenia. Neutrophil count was shown to be dose dependent. Other AEs with a frequency of ≥5% and CTCAE Grade ≥3 considered drug-related were neutropenia (n=24, 42.1%), leukopenia (n=21, 36.8%) and febrile neutropenia (n=5, 8.8%). The mean number of courses was 3.3 across all dose groups at this schedule. 16 or more courses of treatment at this schedule were administered in two patients without evidence of accumulating toxicity. Stable disease as best response was reported in 33.3% of patients. Conclusions: BI 811283 is a selective Aurora B inhibitor with a favorable safety profile. The MTD in the 3-week schedule was 230 mg. An expansion at this dose is ongoing for a full description of the PK and PD of BI 811283, as well as further safety data at this dose level. All data will be taken to consideration for recommendation of the phase II dosage. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim