Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies

3106 Introduction: LBH589 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and inhibits hERG channel with an IC50 of 3.9 μM. Methods: In 2 phase I studies, LBH589 was administered as a 30 minute intravenous infusion on 2 schedules, days 1–3 and 8–10 of a 21 day cycle or days 1–3 and 15–17 of a 28 day cycle to adult pts with advanced solid malignancies (study 2101) or on a schedule of days 1–7 of a 21 day cycle to adult pts with hematologic malignancies (study 2102). Patients with impaired heart function were excluded, and drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (6 ECGs), and on days of dosing. ECG data were processed in a core lab by manual analysis. Results: 45 pts (median age: 60 yrs; 23 males, 22 females) were treated at 10 dose levels, range 1.2 - 20.0 mg/m2/day. PK analysis showed dose proportionality, T1/2 of 6 - 26 hr, and approximately 1.5 fold accumulation at steady state (day 3). PD analysis of PBL showe...