TY - JOUR
T1 - Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas
AU - Kummar, Shivaani
AU - Gutierrez, Martin E.
AU - Chen, Alice
AU - Turkbey, Ismail B.
AU - Allen, Deborah
AU - Horneffer, Yvonne R.
AU - Juwara, Lamin
AU - Cao, Liang
AU - Yu, Yunkai
AU - Kim, Yeong Sang
AU - Trepel, Jane
AU - Chen, Helen
AU - Choyke, Peter
AU - Melillo, Giovanni
AU - Murgo, Anthony J.
AU - Collins, Jerry
AU - Doroshow, James H.
PY - 2011/5
Y1 - 2011/5
N2 - 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 Ktrans and kep 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.
AB - 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 Ktrans and kep 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.
KW - Bevacizumab
KW - Clinical trial
KW - EGF inhibitor
KW - Phase I
KW - VEGF inhibitor
KW - Vandetanib
KW - ZD6474
UR - http://www.scopus.com/inward/record.url?scp=79953682199&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953682199&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2010.12.016
DO - 10.1016/j.ejca.2010.12.016
M3 - Article
C2 - 21247755
AN - SCOPUS:79953682199
SN - 0959-8049
VL - 47
SP - 997
EP - 1005
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 7
ER -