QT Interval Measurements in Patients with Hematologic Malignancies and Solid Tumors Treated with Oral Panobinostat (LBH589).

Panobinostat (LBH589), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor (DACi) with broad anti-tumor activity in preclinical models and promising clinical activity in Phase I/II studies. Prolongation of the QT interval has been reported with DACis, and data on file indicate this is a class effect associated with inhibition of maturation of hERG – a component of potassium ion channels. This analysis represents the first extended evaluation of the incidence of QT prolongation in patients treated with oral, single-agent panobinostat at different doses and schedules.

An analysis was performed on pooled data from eight completed or ongoing Phase I and II studies of single-agent oral panobinostat in patients with advanced hematologic malignancies or solid tumors. The following doses and 28-day cycle dosing schedules were analyzed: doses of 20 to 60 mg/dose administered TIW (Days 1, 3 and 5) weekly (QW), or doses of 30 to 60 mg/dose administered TIW every other week (QOW). Twelve-lead electrocardiograms (ECGs) were performed in triplicate pre- and 3 hours post-dose on Days 1, 5 and 26 in Cycle 1, and as a single reading pre-dose on Days 8 and 15. In subsequent cycles, a single ECG was performed on Day 1 pre-dose. All ECGs were evaluated centrally. QT intervals were corrected individually for heart rate using Fridericia's formula and were reported as absolute QTcF and mean QTcF change from baseline. In addition, a mixed effect model was used to explore the relationships between QTcF change and baseline characteristics within the pooled data of oral, single-agent panobinostat with two schedules – QW and QOW.

Analysis of oral TIW QW dosing is available based on ECGs from 392 patients (241 female/151 male), with a median age of 60 years (range: 16–88), receiving oral panobinostat at 20 mg/dose (n=282), 30 mg/dose (n=22), 40 mg/dose (n=34), or 60 mg/dose (n=54). At panobinostat doses of ≤40 mg/dose, QTcF >500 ms and mean QTcF change from baseline >60 ms on at least one ECG were reported in <1% and 3.5% of patients, respectively. Across these dose levels, 30–50% of patients experienced a clinically non-significant QTcF change of 30 to 60 ms from baseline. At the 60 mg dose level, QTcF >500 ms and mean QTcF change from baseline >60 ms were reported in 5.6% and 9.3% of patients, respectively. Most QT prolongation events occurred in a single ECG and were not persistent over time. No cases of Torsade de pointes were observed with oral panobinostat. A separate analysis of QTcF change from baseline across two schedules was performed on 436 treated patients (178 female/258 male), with a median age of 58 years (range: 16–88), receiving oral panobinostat (20, 30 or 40 mg/dose TIW QW [n=384], and 30 or 60 mg/dose TIW QOW [n=52]). This analysis showed that the greatest mean QTcF changes from baseline were observed on Days 1 and 5 of Cycle 1. Later in the cycle, a trend was noted of QTcF values to return to baseline, with QW dosing.

Absolute QTcF prolongation >500 ms and changes >60 ms from baseline were infrequently reported with weekly administration of oral panobinostat up to 40 mg/dose TIW. These data support a significant reduction of the ECG monitoring schedule in future studies investigating oral panobinostat at doses up to 40 mg/dose on a TIW schedule. ECG monitoring based on the original schedule is ongoing in a clinical trial investigating the oral dose of 60 mg/dose TIW at QW schedule in patients with refractory AML to better characterize the QTcF interval at this dose level.

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