Central ECG analysis of resminostat, a new oral histone deacetylase inhibitor (HDACi), in clinical development as anticancer compound.

Abstract

e13609 Background: Resminostat (4SC-201) is a new, specific, potent, pan-HDAC inhibitor with broad anti-tumor activity in preclinical models and promising clinical characteristics. Methods: 19 patients with advanced solid tumors were treated in a first-in-human trial at increasing oral daily dose levels from 100 mg to 800 mg in repeated 14-day cycles consisting of 5 consecutive treatment days followed by a 9-day rest period. Cardiac function was monitored by pulse rate, blood pressure, troponin levels, and continuous ECG telemetry during the first treatment day. In addition, standard 12-lead rest ECGs were conducted frequently to aid in the determination of potential effects on QT interval prolongation. An intensive profile consisting of 18 single ECGs was performed from day 1 to 5 during cycle 1, and a reduced number of ECGs in the following cycles, if there were no clinically relevant findings. Subsequent to the on-site clinical assessment, ECGs were sent to a core lab for further analysis by a trained cardiologist. PR, QRS, and QT intervals and heart rate (HR) were measured in lead II across 3 consecutive beats using markers for the respective ECG intervals. Results: No signal for drug-induced prolongation of QTc was observed. A dose-dependent increase in HR with a maximum mean increase of up to 22 beats per minute and a corresponding shortening of the PR and QT interval was found. HR correction with Fridericia's formula did not reveal consistent changes in QTc. The incidence of QTcF outliers was very small. The results suggest that resminostat does not affect the duration of myocardial repolarization. At doses ≥ 400 mg, unspecific flattening of the T-wave and slight depression of the ST-segment were observed frequently. However, in some patients such findings were already observed at baseline. No dose-limiting toxicities were seen with regard to cardiac safety in all dose cohorts. Conclusions: Central analysis of phase I ECG measurements did not reveal a drug- induced prolongation of the QTc interval. Drug administration was frequently associated with moderate increases in HR. At higher doses ≥ 400 mg unspecific changes in T-wave morphology and slight ST-segment depression were observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 4SC AG 4SC AG 4SC AG 4SC AG