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Background: HDACi have demonstrated activity as anticancer agents and are licensed for use in cutaneous and peripheral T cell lymphoma. Cardiac effects including arrhythmias and QTc prolongation have previously been associated with HDACi administration in humans. This report summarizes the cardiac adverse event (AE) profile observed during the recently completed FIH Phase I trial of JNJ26481585. Methods: Continuous oral daily dosing (QD) of JNJ26481585 in 21-day (D) cycles (C) was investigated initially in 20 patients (pts) demonstrating activity (including 1 partial response, 1 minor response, 1 prolonged stable disease in melanoma) but ventricular arrhythmia (2 pt) and fatigue (1 pt) were dose-limiting. To improve tolerability, 3 intermittent schedules (QD Mon/Wed/Fri (MWF); QD Mon/Tue/Wed/Thu (MTWT); QD Mon/Thu (MT)) also in 21-D C were subsequently explored in 38 (including expansion cohort), 19 and 15 pts respectively. All pts had triplicate 12-lead ECG (tECG), 24 hour ECG (Holter) and echocardiography or MUGA scan for assessment of left ventricular ejection fraction (LVEF) at baseline and during treatment. Analysis of mean QTcF, categorical QTcF and preliminary assessment of cardiac rhythm/morphology was performed. Results: 12mg QD MWF was identified as the recommended Phase II dose (RP2D) based on safety, tolerability, PK predictions and PD activity. Maximum average increase in mean QTcF from baseline ranged from 0 to 8 milliseconds (ms) during cycles 1 and 2 across the 4 schedules. At RP2D, the maximum average increase in mean QTcF observed was 6ms. 1 out of 38 pts (2.6%) treated on the MWF schedule experienced a Grade (G) 3 QTcF prolongation, possibly related to ST-T segment changes identified as a class effect of HDACi. QTcF prolongation G1–2 was rarely observed across schedules and mostly occurred as an isolated reversible observation whilst on study drug. Reversible, non-sustained ventricular tachycardia (NSVT) was observed as a dose limiting toxicity (DLT) in 3 out of 39 pts (7.7%) receiving QD or MTWT dosing but was not observed on the MWF or MT schedules. Other reversible, but dose-limiting, cardiac effects were T-wave inversion (2 pts on MT and MTWT), supraventricular tachycardia (1 pt on MT) and hypertension with raised troponin (1 pt on MWF). Non-specific, reversible, asymptomatic ST-T segment changes were frequently observed. LVEF was unaffected during treatment with JNJ26481585. Conclusion: The RP2D of JNJ26481585 was determined as 12 mg on the MWF schedule and demonstrated an acceptable cardiac safety profile. One pt had QTcF>500 ms but no clinically significant effect on the QTcF interval was observed across schedules. Reversible NSVT was identified as a DLT in some patients on the QD and MTWT dosing schedules but not on the MWF and MT schedules. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A164.