title: A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.
authors.affiliation: Department of Medical Oncology, Tumour Biology Center, Breisacherstrasse 117, 79106, Freiburg, Germany. mross.klaus@googlemail.com.|, Waldhofstrasse 50, 19117, Freiburg, Germany. mross.klaus@googlemail.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.affiliation: Department of Medical Oncology, Tumour Biology Center, Breisacherstrasse 117, 79106, Freiburg, Germany.|Department of Hematology and Oncology, University Hospital, Breisacherstr. 117, 79106, Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Frost
authors.affiliation: Department of Medical Oncology, Tumour Biology Center, Breisacherstrasse 117, 79106, Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Scharr
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
authors.forename: Bahar
authors.initials: B
authors.lastname: Nokay
authors.affiliation: ProQinase GmbH, Breisacherstrasse 117, 79106, Freiburg, Germany.|Boehringer Ingelheim Pharma GmbH & Co. KG., Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Graeser
authors.affiliation: Boehringer Ingelheim Ltd., Ellesfield Avenue, Bracknell, Berkshire, RG12 8YS, UK.
authors.forename: Chooi
authors.initials: C
authors.lastname: Lee
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA.|Applied Biomath LLC, Wincester, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hilbert
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG., Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
authors.forename: Rainer-George
authors.initials: RG
authors.lastname: Goeldner
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG., Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fietz
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D053538:Keratin-18; D047428:Protein Kinase Inhibitors; D064107:Aurora Kinase B
keywords: Aurora B kinase; BI 811283; Mitosis modulators; Phase I; Solid tumors