British journal of cancer · 2014
A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies.
Клиническое исследование I фазыСравнительное исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lin C-C, Su W-C, Yen C-J, Hsu C-H, Su W-P, Yeh K-H, Lu Y-S, Cheng A-L, Huang D C-L, Fritsch H, Voss F, Taube T, Yang J C-H
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAgedAntineoplastic AgentsCell Cycle ProteinsCombined Modality TherapyDose-Response Relationship, DrugDrug Administration ScheduleFemaleHalf-LifeHematologic DiseasesHumansInfusions, IntravenousMaleMaximum Tolerated DoseMiddle AgedNeoplasm ProteinsNeoplasmsProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsPteridinesSalvage TherapyTaiwanTreatment OutcomePolo-Like Kinase 1