title: Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia.
abstract: This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo-like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose-limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2-h infusion on days 1 and 15 of a 28-day cycle, with dose escalation following a 3 + 3 design. A total of 19 patients were treated with three volasertib doses: 350, 400 and 450 mg. One patient receiving volasertib 450 mg reported a dose-limiting toxicity of grade 4 abnormal liver function test and 450 mg was determined as the maximum tolerated dose. The most frequently reported adverse events were febrile neutropenia (78.9%), decreased appetite (42.1%), nausea and rash (36.8% each), and sepsis, fatigue, hypokalemia, stomatitis and epistaxis (26.3% each). Best responses were complete remission (n = 3), complete remission with incomplete blood count recovery (n = 3) and partial remission (n = 1). The median remission duration of the six patients with complete remission or complete remission with incomplete blood count recovery was 85 days (range 56-358). Volasertib exhibited multi-compartmental pharmacokinetic behavior with a fast distribution after the end of infusion followed by slower elimination phases. Volasertib monotherapy was clinically manageable with acceptable adverse events and anti-leukemic activity.
authors.affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Fukui, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.affiliation: Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Sakura
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: Clinical Trial Management Department, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Watabe
authors.affiliation: Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd, Hyogo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Harada
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Taube
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007564:Japan; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011621:Pteridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C541363:BI 6727
keywords: Acute myeloid leukemia; Japanese; Polo-like kinase 1; clinical trial phase I; maximum tolerated dose