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

Abstract

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 showed increased histone acetylation for 24 hours post-last dose at doses ≥ 4.8 mg.m2. A total of 1475 post-dose ECGs were performed. Central tendency analysis showed no change in QTcF on day 1; however, on day 3 of dosing, there was a dose related increase in QTcF of at most 20 msec. Frequency of outliers, QTcF > 500 msec and/or > 60 msec change from baseline, was 28% (12 pts) and occurred over a broad dose range, 4.8 mg/m2 - 20.0 mg/m2. Outlier ECGs occurred primarily on day 3 (7/12 pts) or later (3/12 pts) on days 4 or 5). Only 2 pts had outliers ECG on day 1. Six patients (14%) had QTc > 500 msec. Frquency of QTcF > 500 msec increased with dose. At doses ≤ 9 mg/m2, only 1 patient (1/33) had QTcF > 500 msec; while at doses > 9 mg/m2, 5 of 12 patients had QTcF > 500 msec. T wave and ST-T wave changes, primarily T wave flattening were frequently observed and were non-specific.Conclusions: LBH589 is a novel, potent HDAC inhibitor which was found to induce dose-related increases in QTcF of 20 msec or less at doses up to 20.0 mg/m2. Cardiac repolarization changes were delayed until day 3 perhaps due to a different mechanism effecting the hERG channel. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis