Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors

Drevs, Joachim and Siegert, Patrizia and Medinger, Michael and Mross, Klaus and Strecker, Ralph and Zirrgiebel, Ute and Harder, Jan and Blum, Hubert and Robertson, Jane and Jürgensmeier, Juliane M. and Puchalski, Thomas A. and Young, Helen and Saunders, Owain and Unger, Clemens. (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology, 25 (21). pp. 3045-3054.

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Official URL: http://edoc.unibas.ch/43933/

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AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.; In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.; Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.; Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
Faculties and Departments:03 Faculty of Medicine
UniBasel Contributors:Medinger, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Clinical Oncology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Oct 2017 09:07
Deposited On:04 Oct 2017 09:07

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