Cardiac monitoring in phase I trials of a novel histone deacetylase (HDAC) inhibitor LAQ824 in patients with advanced solid tumors and hematologic malignancies

Abstract

3131 Introduction: LAQ824, a novel cinnamic acid hydroxamate, inhibits HDAC activity (IC50, 0.03 μM) and the hERG channel(IC50, 10 μM). Methods: In 3 phase I studies, LAQ824 was administered as a 3-hr intravenous infusion on several dosing schedules, principally days 1–3 of a 21-day cycle, to adult pts with advanced solid (studies 2102 and 2107) or hematologic (study 2101) malignancies. Pts with impaired cardiac function were excluded; drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (4 ECGs), on days of dosing and post-dose each cycle. ECG data were processed in a core lab by manual analysis. Cardiac enzymes were assessed on days of dosing. LVEF was assessed by MUGA scan or echocardiogram each cycle. Results: 77 pts (median age: 60 yrs; 48 males, 29 females) were treated at 11 dose levels, range 6 - 200 mg/m2/day. PK analysis showed dose proportionality, T1/2of 6 - 26 hrs, and 1.5 fold accumulation at steady state. There was considerable inter-patient variability in PKs and 4 pts (5%) had exposures > 10x cohort mean. Sustained histone acetylation was noted in PBL 24 hrs post-last dose at doses ≥36 mg/m2. Central tendency analysis of 2576 post-dose ECGs showed no changes in QTcF on day 1; however, there was a dose-related increase in QTcF of < 20 msec on day 3. Frequency of outliers, % of patients with at least 1 ECG with QTcF > 60 msec change from baseline, was 10% (8 pts) and occurred over a broad dose range (36 - 200 mg/m2). Outlier ECGs occurred primarily on day 3 (6/8 pts). There were no outliers on day 1. None of the pts with high LAQ824 plasma exposures had outlier ECGs. Only 1 pt had QTc > 500 msec; in cycle 1 after dosing at 200 mg/m2, and after dose reduction to 125 mg/m2 in cycle 2, a 10 sec. run of unsustained torsades de pointes. Non-specific T wave flattening occurred frequently. Two pts had small, transient increases in troponin without increase of CK MB. There were no significant changes in LVEF.Conclusions: LAQ824, a novel HDAC inhibitor, was found to induce dose-related increases in QTcF of < 20 msec at doses up to 200 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 AstraZeneca, Boehringer Ingleheim, Celgene, Novartis, Oncolytics Biotech GlaxoSmithKline, Merck, Novartis, Roche Novartis