A Phase II Study of Hepatic Arterial Infusion With Floxuridine and Dexamethasone in Combination With Intravenous Bevacizumab (A Monoclonal Antibody to Vascular Endothelial Growth Factor-A), in Patients With Unresectable Primary Hepatic Malignancy
- Determine the median time to progression in patients with unresectable primary hepatic
malignancy treated with hepatic arterial infusion comprising floxuridine and
dexamethasone in combination with systemic bevacizumab.
- Determine the utility of dynamic contrast-enhanced MRI (DCE-MRI) for assessing changes
in tumor perfusion before and during treatment.
- Correlate DCE-MRI findings with radiographic tumor response.
- Correlate the expression patterns of vascular endothelial growth factor (VEGF) receptor
(VEGFR)-1, VEGFR-2, and VEGFR-3 and their cognate ligands (including VEGF-A, VEGF-B,
VEGF-C, VEGF-D, and placenta growth factor [PlGF]) with disease progression and
survival after therapy.
- Assess the pro-angiogenic activity of peripheral blood before and during treatment.
- Assess tumors for immunohistochemical markers of hypoxia (e.g., hypoxia-inducible
factor [HIF-1α], carbonic anhydrase IX [CA IX], and glucose transporters [Glut-1 and
Glut-3]) for correlation with initial and treatment-related changes in perfusion and
permeability, as determined by DCE-MRI.
OUTLINE: This is an open-label, nonrandomized study.
Patients undergo placement of the hepatic arterial infusion (HAI) pump and a
cholecystectomy. Approximately 2 weeks later, patients receive floxuridine and dexamethasone
by HAI continuously on days 1-14 and bevacizumab IV over 30-90 minutes on day 15 of course 1
and on days 1 and 15 of all subsequent courses. Courses repeat every 4 weeks in the absence
of disease progression or unacceptable toxicity.
Patients undergo dynamic contrast-enhanced MRI (DCE-MRI) on days 1 and 15 of course 1 and
then every 8 weeks thereafter.
Tumor and nontumor tissue is collected at the time of the HAI pump placement. Tissue is
examined for the expression of vascular endothelial growth factor (VEGF)-A, -B, -C, and -D,
placenta growth factor (PlGF), and VEGF receptor (VEGFR)-1, -2, and -3 by
immunohistochemistry. Peripheral blood is collected at baseline and on day 1 of each course.
Plasma levels of VEGF-A, -B, -C, and -D are measured by immunoenzyme techniques. Blood is
also examined by flow cytometry and immunological methods and by protein extraction and
analysis of VEGF and VEGFR expression (by western blot). Immunohistochemical markers of
hypoxia in tissue, including hypoxia-inducible factor (HIF-1α), carbonic anhydrase IX (CA
IX), glucose transporters (Glut-1 and Glut-3), and Ki-67 are assessed.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 55 patients will be accrued for this study.
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Antitumor efficacy (complete and partial response, stable and progressive disease)
William R. Jarnagin, MD
Memorial Sloan-Kettering Cancer Center
United States: Institutional Review Board
|Memorial Sloan-Kettering Cancer Center||New York, New York 10021|
|New York Weill Cornell Cancer Center at Cornell University||New York, New York 10021|