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A phase I trial investigating the Aurora B kinase inhibitor BI 811283 in combination with cytarabine in patients with acute myeloid leukaemia
Author(s) -
Döhner Hartmut,
MüllerTidow Carsten,
Lübbert Michael,
Fiedler Walter,
Krämer Alwin,
Westermann Jörg,
Bug Gesine,
Schlenk Richard F.,
Krug Utz,
Goeldner RainerGeorg,
Hilbert James,
Taube Tillmann,
Ottmann Oliver G.
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15563
Subject(s) - cytarabine , medicine , myeloid leukaemia , myeloid , chronic myeloid leukaemia , myeloid leukemia , oncology , pharmacology
BI 811283, an adenosine triphosphate-competitive, reversible and potent inhibitor of Aurora B kinase, has demonstrated anti-tumour activity in acute myeloid leukaemia (AML) cell lines (G€ urtler et al, 2010a,b; Tontsch-Grunt et al, 2010; Mross et al, 2016). Here we report a phase I trial that evaluated the maximum tolerated dose (MTD), safety, efficacy and pharmacokinetics (PK) of BI 811283 with low-dose cytarabine (LDAC) in AML patients considered ineligible for intensive treatment. Patients with previously untreated (except with hydroxycarbamide) or relapsed/refractory AML (excluding acute promyelocytic leukaemia) considered unsuitable for intensive induction or salvage therapy were randomised to one of two schedules, combining BI 811283 (24-h intravenous infusion; 4-week cycle) with LDAC (20 mg twice daily subcutaneously; days 1–10 of a 4-week cycle). In Schedule A, patients received BI 811283 on days 1 and 15. In Schedule B, patients received BI 811283 on day 1. BI 811283 dose escalation followed a 3 + 3 design (BI 811283 starting dose: 5 mg). The primary endpoint was to determine the MTD of the two BI 811283 schedules in combination with LDAC based on the incidence of dose-limiting toxicities (DLTs). Further endpoints included: incidence and intensity of adverse events (AEs), response and PK of cytarabine with BI 811283. Full methodological details are provided in Appendix S1. All patients provided written informed consent and the trial was registered with ClinicalTrials.gov: NCT00632749. Of 68 randomised patients, 64 were treated (Schedule A, n = 28; Schedule B, n = 36). At baseline (Table SI), 11 (17 2%), 37 (57 8%) and 16 (25 0%) patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 and 2, respectively. Median age was 73 (range, 49– 89) years. Forty-four patients (68 8%) were previously untreated for AML and 20 (31 3%) patients had relapsed/refractory disease. Twenty-two patients (34 4%) had adverserisk genetics, two patients (3 1%) had favourable-risk genetics, and 20 (31 3%) and six patients (9 4%) had intermediate-risk I and II genetics, respectively. Dose escalations and DLTs are shown in Table I. In Schedule A, DLTs were seen in the 120 mg dose group; the BI 811283 dose was therefore de-escalated to 100 mg and a further three patients were enrolled. As no DLTs were seen at the 100 mg dose level, the MTD in Schedule A was