Beschreibung:
<jats:title>Abstract</jats:title>
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<jats:title>Purpose</jats:title>
<jats:p>This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker).</jats:p>
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<jats:title>Results</jats:title>
<jats:p>A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease).</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p>BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients.</jats:p>
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<jats:title>Trial registration</jats:title>
<jats:p>EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.</jats:p>
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