A phase i study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies
Journal
British Journal of Cancer
Journal Volume
110
Journal Issue
10
Pages
2434-2440
Date Issued
2014
Author(s)
Su W.-C.
Yen C.-J.
Su W.-P.
Huang D.C.-L.
Fritsch H.
Voss F.
Taube T.
Abstract
Background:Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.Methods:Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.Results:Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ?135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.Conclusions:These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients. ? 2014 Cancer Research UK.
SDGs
Other Subjects
alanine aminotransferase; polo like kinase inhibitor; volasertib; abdominal distension; abdominal pain; adult; advanced cancer; aged; alanine aminotransferase blood level; anemia; article; Asian; decreased appetite; dizziness; drug clearance; drug distribution; drug dose increase; drug effect; drug efficacy; drug half life; drug safety; drug tolerability; dyspnea; fatigue; febrile neutropenia; female; gastrointestinal hemorrhage; human; hypokalemia; ileus; infection; leukopenia; major clinical study; male; maximum tolerated dose; melanoma; neutropenia; pain; phase 1 clinical trial; priority journal; solid tumor; thrombocytopenia; tinnitus; ureter cancer; Adult; Aged; Antineoplastic Agents; Cell Cycle Proteins; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Proteins; Neoplasms; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Salvage Therapy; Taiwan; Treatment Outcome
Publisher
Nature Publishing Group
Type
journal article