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author:("zannis, P.")
1.  Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies 
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.
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/m2) 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).
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.
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.
PMCID: PMC3265736  PMID: 21739119
Anti-tumor; ECG; Malignancies; QTc interval; Trabectedin
2.  A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies 
Annals of Oncology  2008;19(10):1802-1809.
Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
PMCID: PMC2598415  PMID: 18497430
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin

Results 1-2 (2)