A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology 2016-08, Vol.78 (2), p.405-417
• Main Authors: Mross, Klaus, Richly, Heike, Frost, Annette, Scharr, Dirk, Nokay, Bahar, Graeser, Ralph, Lee, Chooi, Hilbert, James, Goeldner, Rainer-George, Fietz, Oliver, Scheulen, Max E.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Aurora Kinase B - antagonists & inhibitors; Cancer Research; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Keratin-18 - blood; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Original; Original Article; Pharmacology/Toxicology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacology; Treatment Outcome; Young Adult
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3095-6

Purpose 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.