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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.


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Colorectal Cancer

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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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum

- Patients receiving bevacizumab must have tumor tissue available for
immunohistochemical analysis

- Formalin-fixed, paraffin-embedded tissue from previous biopsy or surgical
resection is sufficient

- Measurable disease, defined by RECIST as ≥ 1 lesion that can be accurately measured
in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional
techniques (i.e., CT or MRI)

- CEA elevation alone is insufficient for study entry

- No known brain metastases

PATIENT CHARACTERISTICS:

Criteria for all patients

- ECOG performance status 0-1

- Life expectancy > 3 months

- Granulocytes ≥ 1,500/mL

- Platelet Count ≥ 100,000/mL

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- AST ≤ 5 times ULN

- Urine protein:creatinine ratio ≤ 1.0 at screening

- Patients with other prior malignancies are eligible, provided they have been treated
with curative intent and have no evidence of recurrence

- Not pregnant or nursing

- Negative pregnancy test

- No contraindications to MRI, including any of the following:

- Hypersensitivity to gadolinium

- Metallic device, including pacemaker, non-MRI compatible aneurysm clip, other
non-MRI-compatible mechanical and/or electrical device, or metallic fragments

- Severe claustrophobia

Additional criteria for patients receiving bevacizumab:

- No significant traumatic injury within the past 28 days

- No serious nonhealing wounds, ulcers, or bone fractures

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 6 months

- No myocardial infarction, unstable angina, or cerebrovascular accident within the
past 6 months

- No clinically significant peripheral vascular disease

- No New York Heart Association class II-IV congestive heart failure

- Patients with pre-existing hypertension should be on a stable antihypertensive
regimen with blood pressure ≤ 150/100 mm Hg at study entry

PRIOR CONCURRENT THERAPY:

Criteria for all patients

- Prior adjuvant treatment including oxaliplatin allowed

- No prior bevacizumab

- At least 14 days since prior radiotherapy and recovered

- More than 6 months since prior chemotherapy

- No other concurrent investigational agents

Additional criteria for patients receiving bevacizumab:

- At least 28 days since prior major surgical procedure or open biopsy

- At least 7 days since prior minor surgical procedure (e.g., fine-needle aspirations
or core biopsies)

- No anticipation of need for a major surgical procedure during study treatment

- Concurrent oral or parenteral anticoagulation therapy allowed provided dose is stable

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Primary Purpose: Diagnostic

Outcome Measure:

Analysis of tumor blood flow, assessed by DCE-MRI as percentage change in Ktrans, after 2 courses of FOLFOX and bevacizumab or FOLFOX alone compared to baseline value

Safety Issue:

No

Principal Investigator

Amy Kramer, RN, MPA

Investigator Affiliation:

Abramson Cancer Center of the University of Pennsylvania

Authority:

Unspecified

Study ID:

CDR0000580810

NCT ID:

NCT00602329

Start Date:

February 2006

Completion Date:

Related Keywords:

  • Colorectal Cancer
  • recurrent colon cancer
  • recurrent rectal cancer
  • stage III colon cancer
  • stage III rectal cancer
  • stage IV colon cancer
  • stage IV rectal cancer
  • adenocarcinoma of the colon
  • adenocarcinoma of the rectum
  • Colorectal Neoplasms

Name

Location

Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283