MRI in Predicting Response in Patients Receiving Combination Chemotherapy and Bevacizumab For Advanced or Metastatic Colorectal Cancer

Sponsor

Abramson Cancer Center of the University of Pennsylvania (Other)

Overall Status

Terminated

CT.gov ID

NCT00602329

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arms

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may kill more tumor cells. Diagnostic procedures, such as MRI, may help doctors predict a patient's response to treatment and help plan the best treatment.

PURPOSE: This randomized phase II trial is studying how well MRI works in predicting response to combination chemotherapy given together with bevacizumab in treating patients with advanced or metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: bevacizumab Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin	Phase 2

Detailed Description

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

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.

Study Start Date :

Feb 1, 2006

Actual Primary Completion Date :

Jul 1, 2009

Actual Study Completion Date :

Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Biological: bevacizumab Given IV Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Experimental: 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.	Biological: bevacizumab Given IV Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Active Comparator: FOLFOX alone (control) Patients receive FOLFOX as in arm I.	Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV

Arm

Intervention/Treatment

Experimental: 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.

Biological: bevacizumab

Given IV

Drug: fluorouracil

Given IV

Drug: leucovorin calcium

Given IV

Drug: oxaliplatin

Given IV

Experimental: 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.

Biological: bevacizumab

Given IV

Drug: fluorouracil

Given IV

Drug: leucovorin calcium

Given IV

Drug: oxaliplatin

Given IV

Active Comparator: FOLFOX alone (control)

Patients receive FOLFOX as in arm I.

Drug: fluorouracil

Given IV

Drug: leucovorin calcium

Given IV

Drug: oxaliplatin

Given IV

Outcome Measures

Primary Outcome Measures

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 [2 cycles for all subjects]

Secondary Outcome Measures

Analysis of tumor markers of angiogenesis and apoptosis, and the effect of treatment [2 cycles for all subjects]
Correlation of tumor blood flow with time to progression [2 cycles]
Correlation of markers of apoptosis in tumor cells with response to therapy, time to progression, and overall survival [2 cycles for all subjects]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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