Abstract C121: A phase 1 QTc study of tivozanib in patients with advanced solid tumors

Autor: Kathleen N. Moore, Jeffrey R. Infante, Manpreet Chadha, Lindsey Jacobson, Andrew Strahs, Dennis L. Vargo, William Slichenmyer, Monette M. Cotreau
Rok vydání: 2011
Předmět:
Zdroj: Molecular Cancer Therapeutics. 10:C121-C121
ISSN: 1538-8514
1535-7163
Popis: Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Previous preclinical and clinical studies have shown that tivozanib displays strong antiangiogenic and antitumor effects. Preclinical and retrospective electrocardiogram (ECG) analyses did not suggest an effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the proarrhythmogenic potential of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Patients with a repeated baseline QTcF >480 ms were excluded. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20–30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessment of clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received at least one dose of tivozanib were evaluable for the present study. Preliminary adverse event data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib at 1.5 mg daily over a 21-day period does not cause clinically significant prolongation of QT/QTc over baseline. Data from this study suggest that the safety and PK profile of tivozanib was similar to that observed in previous studies, and that the findings are consistent with the ECG evaluation in a monkey telemetry study. 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 C121.
Databáze: OpenAIRE
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