Phase I Clinical Trial Evaluating the Toxicity, Pharmacokinetics and Biological Effect of Intravenous Bevacizumab (Avastin TM) in Combination With Escalating Doses of Oral AZD2171 for Patients With Advanced Malignancies
I. To evaluate the safety and toxicity profile of intravenous bevacizumab (avastin)
administered in combination with oral AZD2171 (cediranib maleate) for patients with advanced
II. To determine the pharmacokinetic profile of oral AZD2171 in combination with bevacizumab
(avastin) administered to patients with advanced malignancies.
I. To evaluate the serum concentrations of Nitric Oxide (NO) and Nitric oxide synthase (NOS)
among patients treated with this regimen and to correlate with VEGF expression.
II. To determine changes in the tumor vasculature detected by DCE-MRI among patients treated
with this combination of VEGF receptor blocking agents.
III. To evaluate the potential predictive role of angiogenesis molecular endpoints in
malignant effusion samples.
IV. To assess in a descriptive fashion the efficacy of the studied regimen.
OUTLINE: This is a dose-escalation study.
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib
maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Blood samples are acquired at baseline, on day 2, and after 2 courses of treatment for
pharmacokinetic studies. Samples are analyzed by TUNEL, immunofluorescence staining,
laser-scanning cytometry, flow cytometry, enzyme-linked immunosorbent assay, and
immunohistochemistry to assess apoptosis in tumor and endothelial cells, microvessel density
mean vessel volume, nitric oxide concentration, and signal transduction pathways (i.e., ERK
½, P38 mitogen-activated protein kinase, protein kinase B, circulating endothelial and
progenitor cells, basic fibroblast growth factor, vascular endothelial growth factor (VEGF)
receptor phosphorylation, VEGF, and hypoxia inducible factor-1α). Some patients also undergo
tissue biopsy at baseline and after 2 courses of treatment for characterization of vascular
and angiogenesis markers. Some patients also undergo DCE-MRI at baseline, once between days
22-24, and after every 2 courses of treatment to assess blood perfusion.
After completion of study treatment, patients are followed for 6 weeks.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and toxicity profile of combination bevacizumab and cediranib maleate
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
Up to 6 weeks post-treatment
M.D. Anderson Cancer Center
United States: Food and Drug Administration
|M D Anderson Cancer Center||Houston, Texas 77030|