RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining monoclonal antibody therapy with combination chemotherapy may kill more tumor cells. It is not yet known if bevacizumab is more effective with or without combination chemotherapy in treating colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without bevacizumab in treating patients who have advanced or metastatic colorectal cancer that has been previously treated.

Condition	Treatment or Intervention	Phase
stage III colon cancer stage IV colon cancer stage III rectal cancer Stage IV rectal cancer recurrent colon cancer recurrent rectal cancer adenocarcinoma of the colon adenocarcinoma of the rectum	Drug: bevacizumab  Drug: fluorouracil  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: growth factor antagonist therapy  Procedure: monoclonal antibody therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the response, time to progression, and overall survival of patients with previously treated advanced or metastatic colorectal adenocarcinoma treated with oxaliplatin, leucovorin calcium, and fluorouracil with or without bevacizumab versus bevacizumab only. (Arm III closed to accrual as of 03/11/2003).
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized study. Patients are stratified according to ECOG performance status (0 vs 1 or 2), and prior radiotherapy (yes vs no). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1 and 2.
• Arm II: Patients receive oxaliplatin, leucovorin calcium, and 5-FU as in arm I.
• Arm III: Patients receive bevacizumab as in arm I. (Arm closed to accrual as of 03/11/2003). Courses in all arms repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response may receive 2 additional courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 880 patients (293 per treatment arm) will be accrued for this study within 18 months. (Arm III closed to accual as of 03/11/2003).

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum
• Advanced or metastatic disease
• Must have received a fluoropyrimidine-based regimen and an irinotecan-based regimen, either alone or in combination, for advanced disease
• May have relapsed within 6 months of adjuvant therapy with fluorouracil (5-FU) (or combination 5-FU and irinotecan) and progressed after single-agent irinotecan
• Measurable disease
• No known brain metastases

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No history of thrombotic or hemorrhagic disorders

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST no greater than 5 times ULN
• INR no greater than 1.5
• PTT no greater than ULN

Renal:

• Creatinine no greater than 1.5 times ULN
• Proteinuria less than 1+ (i.e., 0 or trace) OR
• Protein less than 500 mg by 24-hour urine collection
• Proteinuria secondary to ureteral stents allowed
• No proteinuria secondary to nephropathy

Cardiovascular:

• Controlled hypertension (less than 150/100 mm Hg) allowed if on a stable antihypertensive regimen
• No prior myocardial infarction
• No uncontrolled congestive heart failure
• No unstable angina within the past 3 months

Other:

• No serious nonhealing wound, ulcer, or bone fracture
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior bevacizumab

Chemotherapy:

• See Disease Characteristics
• Recovered from prior chemotherapy
• No prior oxaliplatin

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 2 weeks since prior radiotherapy and recovered

Surgery:

• At least 28 days since prior major surgical procedure

Other:

• At least 10 days since prior aspirin dose of more than 325 mg/day
• No concurrent therapeutic anticoagulation except prophylactic anticoagulation of venous access device
• No concurrent antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, or cilostazol)
• No concurrent oral cryotherapy on day 1 of oxaliplatin administration

Arizona
      CCOP - Scottsdale Oncology Program, Scottsdale,  Arizona,  85259-5404,  United States
Colorado
      CCOP - Colorado Cancer Research Program, Inc., Denver,  Colorado,  80224,  United States
Delaware
      CCOP - Christiana Care Health Services, Wilmington,  Delaware,  19899,  United States
Florida
      Veterans Affairs Medical Center - Gainesville, Gainesville,  Florida,  32608-1197,  United States
Georgia
      Veterans Affairs Medical Center - Atlanta (Decatur), Decatur,  Georgia,  30033,  United States
Illinois
      CCOP - Carle Cancer Center, Urbana,  Illinois,  61801,  United States
      CCOP - Central Illinois, Decatur,  Illinois,  62526,  United States
Indiana
      CCOP - Northern Indiana CR Consortium, South Bend,  Indiana,  46601,  United States
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5289,  United States
      Veterans Affairs Medical Center - Indianapolis (Roudebush), Indianapolis,  Indiana,  46202,  United States
Iowa
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States
      Genesis Medical Center, Davenport,  Iowa,  52804,  United States
      Hematology Oncology Associates of the Quad Cities, Bettendorf,  Iowa,  52722,  United States
Louisiana
      CCOP - Ochsner, New Orleans,  Louisiana,  70121,  United States
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
      Tuft-New England Medical Center, Boston,  Massachusetts,  02111,  United States
Michigan
      CCOP - Ann Arbor Regional, Ann Arbor,  Michigan,  48106,  United States
      CCOP - Kalamazoo, Kalamazoo,  Michigan,  49007-3731,  United States
Minnesota
      CCOP - Duluth, Duluth,  Minnesota,  55805,  United States
      CCOP - Metro-Minnesota, Saint Louis Park,  Minnesota,  55416,  United States
Nebraska
      CCOP - Missouri Valley Cancer Consortium, Omaha,  Nebraska,  68106,  United States
New Jersey
      Cancer Institute of New Jersey, New Brunswick,  New Jersey,  08903,  United States
North Dakota
      CCOP - Merit Care Hospital, Fargo,  North Dakota,  58122,  United States
Ohio
      CCOP - Toledo Community Hospital, Toledo,  Ohio,  43623-3456,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Oklahoma
      CCOP - Oklahoma, Tulsa,  Oklahoma,  74136,  United States
Pennsylvania
      Fox Chase Cancer Center, Philadelphia,  Pennsylvania,  19111,  United States
      University of Pennsylvania Cancer Center, Philadelphia,  Pennsylvania,  19104,  United States
South Dakota
      CCOP - Sioux Community Cancer Consortium, Sioux Falls,  South Dakota,  57104,  United States
Tennessee
      Veterans Affairs Medical Center - Tennessee Valley Healthcare System - Nashville Campus, Nashville,  Tennessee,  37212-2637,  United States
Texas
      CCOP - Scott and White Hospital, Temple,  Texas,  76508,  United States
Wisconsin
      CCOP - Marshfield Medical Research and Education Foundation, Marshfield,  Wisconsin,  54449,  United States
      CCOP - St. Vincent Hospital Cancer Center, Green Bay, Green Bay,  Wisconsin,  54301,  United States
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-0001,  United States
Puerto Rico
      MBCCOP - San Juan, San Juan,  00927-5800,  Puerto Rico
      Veterans Affairs Medical Center - San Juan, San Juan,  00927-5800,  Puerto Rico
South Africa
      Pretoria Academic Hospitals, Pretoria,  0001,  South Africa

Study chairs or principal investigators

Bruce J. Giantonio, MD,  Study Chair,  Kimmel Cancer Center (KCC)   

Study ID Numbers:  CDR0000068951; E-3200; CTSU
Record last reviewed:  April 2003
Last Updated:  October 13, 2004
Record first received:  October 11, 2001
ClinicalTrials.gov Identifier:  NCT00025337
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08