title: A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia.
abstract: Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade ≥3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group.
authors.affiliation: Department of Medicine, Haematology and Oncology, University of Münster, Münster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Holger
authors.initials: H
authors.lastname: Fritsch
authors.forename: Gerd
authors.initials: G
authors.lastname: Munzert
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: Frank
authors.initials: F
authors.lastname: Fleischer
authors.forename: Tillmann
authors.initials: T
authors.lastname: Taube
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome; 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; C518477:BI 2536
keywords: Phase I/II trial; Plk inhibitor; acute myeloid leukaemia; non-intensive