In:
Cancer Chemotherapy and Pharmacology, Springer Science and Business Media LLC, Vol. 78, No. 2 ( 2016-08), p. 405-417
Abstract:
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. Methods 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). Results 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). Conclusions BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. Trial registration EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.
Type of Medium:
Online Resource
ISSN:
0344-5704
,
1432-0843
DOI:
10.1007/s00280-016-3095-6
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2016
detail.hit.zdb_id:
6820-2
detail.hit.zdb_id:
1458488-8
SSG:
15,3
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