Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours

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Abstract

The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300–1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration–time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses ⩾750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.

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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