Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies

R Thertulien, G M Manikhas, L Y Dirix, J B Vermorken, K Park, M M Jain, J J Jiao, J Natarajan, T Parekh, P Zannikos, A P Staddon, R Thertulien, G M Manikhas, L Y Dirix, J B Vermorken, K Park, M M Jain, J J Jiao, J Natarajan, T Parekh, P Zannikos, A P Staddon

Abstract

Purpose: The primary objective of this study was to access the potential effects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors.

Methods: Patients (n = 75) who had received ≤3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m(2)) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc (ΔQTc) were assessed. The difference in ΔQTc between trabectedin and placebo was calculated at each time point (ΔΔQTc).

Results: The upper limits of the 90% confidence interval for ΔΔQTcF and ΔΔQTcB at all time points were less than the prespecified noninferiority margin of 10 ms (≤6.65 ms). No patient had a QTc > 500 ms or a time-matched increase from baseline in QTc > 60 ms at any time point. Regression analyses indicated ΔΔQTc was poorly correlated with trabectedin concentration. No adverse events suggestive of proarrhythmic potential were reported.

Conclusion: Trabectedin did not prolong the QTc interval. Safety and pharmacokinetic profiles of trabectedin were similar to that observed in other ovarian and breast cancer studies.

Trial registration: ClinicalTrials.gov NCT00786838.

Figures

Fig. 1
Fig. 1
Placebo-adjusted least square mean (±90% confidence interval) change from baseline in QTc (ΔΔQTc) intervals following treatment with a single dose of trabectedin 1.3 mg/m2 (3-h infusion) in patients with advanced solid tumor malignancies
Fig. 2
Fig. 2
Correlation between placebo-adjusted change from baseline in QTc (ΔΔQTc) versus concentrations of trabectedin in plasma at corresponding time points following treatment with a single dose of trabectedin 1.3 mg/m2 (3-h infusion) in patients with advanced solid tumor malignancies

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