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


METHODS
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.


CONCLUSIONS
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.
Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA. kummars@mail.nih.gov
Shivaani
S
Kummar
Martin E
ME
Gutierrez
Alice
A
Chen
Ismail B
IB
Turkbey
Deborah
D
Allen
Yvonne R
YR
Horneffer
Lamin
L
Juwara
Liang
L
Cao
Yunkai
Y
Yu
Yeong Sang
YS
Kim
Jane
J
Trepel
Helen
H
Chen
Peter
P
Choyke
Giovanni
G
Melillo
Anthony J
AJ
Murgo
Jerry
J
Collins
James H
JH
Doroshow
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D003287:Contrast Media / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003287:Contrast Media; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D004815:Epidermal Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib
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