Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours
Introduction
As first recognised by Folkman in 1971 [1], angiogenesis is fundamental to tumour growth and metastasis. Angiogenesis is implicated in the initial progression from a premalignant tumour to a cancer [2], haematological dissemination [3] and in the growth of dormant micrometastases into overt metastatic lesions [4]. In recent years, several drugs designed to inhibit angiogenesis and thus tumour growth have entered clinical trials with the role of antiangiogenic therapy as cancer treatment under extensive review [5], [6], [7].
Of the numerous growth factors and cytokines shown to have angiogenic activity, the VEGF family of ligands (VEGF-A, -B, -C, -D, and -E), which act through the VEGF family of receptors (VEGFR-1, -2, and -3) [8], [9], are key mediators of tumour-induced neovascularisation and enhancement of vascular permeability [10], [11]. The VEGF receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR), which are predominantly located on proliferating endothelial cells, are upregulated during neovascularisation. Binding of any of five VEGF ligands to any of the three VEGF receptors activates the receptor tyrosine kinase, triggering signaling pathways that stimulate endothelial cell proliferation, migration and tube formation. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation [12]. In several preclinical models, PTK/ZK caused a significant decrease in vessel permeability, an increase in tumour blood volume and a reduction in tumour vessel density [12], [13]. In the current report, we describe the first clinical, pharmacokinetic (PK) and correlative laboratory findings from a phase I study of PTK/ZK monotherapy in patients with liver metastasis secondary to solid tumours.
Section snippets
Patients
Patients with breast or colorectal carcinoma and liver metastasis for which no standard curative therapy was available were eligible for this study. The liver metastasis was evaluated for tumour size and blood flow by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Doppler ultrasound examination. Other inclusion criteria were WHO performance score ⩽2, an estimated life expectancy ⩾3 months and adequate bone marrow function, renal function and liver function defined as
Patients
A total of 27 patients were enrolled onto this trial and were treated until disease progression or unacceptable toxicity occurred, with the exception of 7 patients who discontinued therapy with PTK/ZK as a result of a temporary clinical hold due to unexpected preclinical findings. The trial was resumed after it was established that similar effects did not occur in clinical trials. Patient demographics and baseline disease characteristics are shown in Table 1. Approximately 85% of patients had
Discussion
This study was primarily designed to assess the safety and pharmacokinetic profiles of PTK/ZK in patients with liver metastasis and to establish a recommended best effective dose for phase II and III trials. For this reason, analyses of tumour blood supply and serum biomarkers of angiogenic activity were incorporated into the study protocol to provide further clinical guidance for recommendation of a selected dose for phase II and III trials. We have demonstrated that PTK/ZK, when administered
Conflict of interest statement
This work was supported by Schering AG, Berlin, and the Foundation “Kirstins Weg,” Neuwied, Germany. The study was done in collaboration with Novartis Pharmaceuticals Corporation.
Acknowledgements
The authors thank Martina Pöthig of Schering AG; and Mildred Kowalski, RN,MPA; Bee-Lien Chen, PhD; Dirk Reitsma, MD; Margaret Dugan, MD; and Andrew Henry, MD, of Novartis Pharmaceuticals for their support on this project.
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