Trial Information

A Phase II Study Assessing Tumor Blood Flow as Measured by Dynamic Contrast Enhanced MRI in Patients With Metastatic Colorectal Cancer Receiving FOLFOX Alone Versus Patients Randomized to Receive FOLFOX Plus Bevacizumab at 5mg/kg or 10mg/kg.

OBJECTIVES:

Primary

- To determine the alteration of tumor blood flow using dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI) in patients with advanced or metastatic colorectal
cancer after 2 courses of combination chemotherapy comprising oxaliplatin,
fluorouracil, and leucovorin (FOLFOX) and bevacizumab at 5 mg/kg vs 10 mg/kg or FOLFOX
alone.

Secondary

- To correlate tumor blood flow, as assessed by DCE-MRI, with time to progression in
patients receiving bevacizumab at 5mg/kg vs 10mg/kg.

- To correlate vascular proliferation, as measured by DCE-MRI, with markers of
endothelial cell proliferation (i.e., CD31, 34, 105; integrin αvß3; phospho-ERK; Ki67;
PCNA; and smooth muscle actin).

- To obtain pilot data on whether assays that measure vascular endothelial cell mitogenic
stimulation and mitogenic activity may predict response to therapy, time to
progression, and overall survival of patients receiving bevacizumab at 5mg/kg vs
10mg/kg.

- To investigate the association of various markers of apoptosis in tumor cells (e.g.,
MIF, CREB, or HIF-1-alpha expression/polymorphism and others) and tumor vascularity, as
assessed by DCE-MRI.

- To correlate markers of apoptosis in tumor cells with response to therapy, time to
progression, and overall survival.

- To determine serum levels of VEGF prior to the initiation of chemotherapy and then
prior to courses 2 and 3 of chemotherapy as potential markers of antiangiogenic
activity.

OUTLINE: Patients who are eligible to receive bevacizumab are randomized to 1 of 2 treatment
arms. Patients who are ineligible to receive bevacizumab receive FOLFOX alone.

- Arm I: Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2
hours on day 1 and fluorouracil IV continuously over 46 hours (FOLFOX) beginning on day
1. Patients also receive bevacizumab at 5 mg/kg IV over 90 minutes on day 1. Treatment
repeats every 14 days for 6 months in the absence of disease progression or
unacceptable toxicity.

- Arm II: Patients receive FOLFOX as in arm I and bevacizumab at 10 mg/kg IV over 90
minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of
disease progression or unacceptable toxicity.

- FOLFOX alone (control): Patients receive FOLFOX as in arm I. All patients undergo
dynamic contrast-enhanced MRI at baseline and between courses 2 and 3 (between days 17
and 29) to assess tumor blood flow.

Tumor tissue specimens are obtained from prior colonoscopic biopsy or surgical resection in
patients receiving bevacizumab. Tissue specimens are examined by immunohistochemistry to
evaluate tumor markers of angiogenesis and apoptosis (e.g., CD31, 34, 105, phospho-ERK,
PCNA, Ki67, SMA, and integrin αvß3). Blood specimens are obtained at baseline and prior to
courses 2 and 3 (days 15 and 29) to evaluate plasma levels of VEGF.

After completion of study therapy, patients are followed every 2 months for 1 year and then
every 3 months thereafter.