Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas

Abstract

Purpose: Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF.

Experimental design: Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design.

Results: Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI.

Conclusion: In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Conflict of interest statement

Conflict of interest statement: None declared.

Published by Elsevier Ltd.

Figures

Fig. 1

Changes in tumour size from baseline assessed according to Response Evaluation Criteria in Solid Tumors (n = 13). One patient had nonmeasurable disease, and one patient was not evaluable for response (declined treatment after cycle 1).

Fig. 2

(A) Numbers of circulating endothelial cells (CECs) × 10−3 and (B) circulating endothelial progenitors (CEPs) per 106 PBMCs were determined pre- and post-treatment by 7-parameter flow cytometric analysis. No cycle 2 day 1 sample was available for patient 10, and no cycle 4 day 1 sample was available for patients 5 and 9 through 15. Symbols indicate patients with prolonged disease stabilization (*), minor response (†), or partial response (‡).

Fig. 3

Changes in tumour vascular permeability were assessed using DCE-MRI; parameters were determined before and after treatment. Quantitative analyses of (A) Ktrans, the forward contrast transfer rate, (B) kep, the reverse contrast transfer rate were derived using a curve-fitting general kinetic model (GKM) algorithm. Symbols indicate patients with prolonged disease stabilization (*), minor response (†), or partial response (‡).