RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether monoclonal antibody therapy is more effective with or without irinotecan in treating metastatic colorectal cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without irinotecan plus monoclonal antibody therapy in treating patients who have metastatic colorectal cancer.

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

Further Study Details: 

OBJECTIVES: I. Evaluate the efficacy, in terms of duration of survival, time to disease progression, objective response rate, and duration of objective response of bevacizumab (rhuMAb VEGF) with fluorouracil, leucovorin calcium, and irinotecan as opposed to placebo with fluorouracil, leucovorin calcium, and irinotecan in patients with metastatic colorectal cancer. II. Evaluate the safety of these regimens in these patients. III. Determine the plasma pharmacokinetics of irinotecan with fluorouracil, leucovorin calcium, and bevacizumab (rhuMAb VEGF) versus irinotecan with fluorouracil and leucovorin calcium in these patients. IV. Determine the pharmacokinetics of bevacizumab (rhuMAb VEGF) in these patients. V. Evaluate and compare the quality of life in patients treated with these regimens.

PROTOCOL OUTLINE: This is a randomized, active-controlled, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), site of primary disease (colon vs rectum), and number of metastatic sites (1 vs more than 1). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive irinotecan IV over 90 minutes followed by leucovorin calcium IV over 1-2 minutes and fluorouracil IV over 1-2 minutes weekly for 4 weeks. Patients also receive placebo IV over 30-90 minutes every other week. Courses repeat every 6 weeks. Arm II: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in arm I. Patients also receive bevacizumab (rhuMAb VEGF) IV over 30-90 minutes every other week. Courses repeat every 6 weeks. Treatment continues for a maximum of 16 courses in the absence of disease progression or unacceptable toxicity. All patients with progressive disease may continue to receive treatment on this study with another chemotherapy agent with or without bevacizumab (rhuMAb VEGF). Patients in arm I with progressive disease may continue to receive another chemotherapy agent and are not allowed to receive bevacizumab (rhuMAb VEGF). Patients in arm II with progressive disease may continue to receive bevacizumab (rhuMAb VEGF) alone or in combination with another chemotherapy agent. Patients are followed every 4 months for survival.

PROJECTED ACCRUAL: Approximately 900 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically confirmed metastatic colorectal cancer
• At least 2 bidimensionally measurable lesions
• No CNS disease (e.g., primary brain tumor, seizures not controlled with standard therapy, or any brain metastases)
• No clinically detectable ascites

--Prior/Concurrent Therapy--

• Biologic therapy: No prior biologic therapy for colorectal cancer
• Chemotherapy: At least 12 months since prior fluoropyrimidines with leucovorin and/or levamisole; No other prior chemotherapy
• Endocrine therapy: Not specified
• Radiotherapy: At least 14 days since prior radiotherapy; No prior radiotherapy to any indicator lesion
• Surgery: At least 28 days since prior surgical procedure; At least 7 days since prior fine needle aspiration; No concurrent major surgical procedure
• Other: At least 10 days since prior full-dose oral or parenteral anticoagulants except to maintain patency of pre-existing, permanent indwelling IV catheters; At least 10 days since prior full-dose oral or parenteral thrombolytic agent; At least 28 days since participation in other experimental drug study; No chronic, daily aspirin or nonsteroidal anti-inflammatory medications; No concurrent full-dose oral or parenteral anticoagulants (except for indwelling IV catheter maintenance) or thrombolytic agent

--Patient Characteristics--

• Age: 18 and over
• Performance status: ECOG 0-1
• Life expectancy: More than 3 months
• Hematopoietic: Absolute neutrophil count at least 1,500/mm3; Platelet count at least 75,000/mm3; Hemoglobin at least 9 g/dL (may be transfused); No bleeding diathesis or coagulopathy
• Hepatic: AST or ALT no greater than 2.5 times upper limit of normal (ULN) (less than 5 times ULN if liver metastasis present); Bilirubin no greater than 1.6 mg/dL; International normalized ratio less than 1.5
• Renal: Creatinine no greater than 2.0 mg/dL; No proteinuria or clinically significant impairment of renal function
• Cardiovascular: No clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction, or unstable angina within past year; No New York Heart Association class II-IV congestive heart failure within past year; No serious cardiac arrhythmia requiring medication or grade II or greater peripheral vascular disease within past year
• Other: Must be able to tolerate CT scan contrast dye; No other invasive malignancy within past 5 years except basal cell skin cancer; No CNS disease including uncontrolled seizures or stroke; No active infection requiring parenteral antibiotics; No serious nonhealing wound, ulcer, or bone fracture; No other disease or medical condition that would preclude study; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception

Alabama
      Carraway Cancer Center, Birmingham,  Alabama,  35234,  United States
      Medical Center East, Birmingham,  Alabama,  35235-3401,  United States
      University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham,  Alabama,  35294-3300,  United States
      US Oncology, Birmingham Hematology and Oncology Associates, Alabaster,  Alabama,  35007,  United States
Arkansas
      Highlands Oncology Group, P.A., Fayetteville,  Arkansas,  72703,  United States
California
      Alan B. Newman MD and Associates, San Francisco,  California,  94115,  United States
      Alta Bates Comprehensive Cancer Center, Berkeley,  California,  94704,  United States
      Hoag Memorial Hospital Presbyterian, Newport Beach,  California,  92658,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Kaiser Permanente Medical Center - Vallejo, Vallejo,  California,  94589,  United States
      Kaiser Permanente-Southern California Permanente Medical Group, San Diego,  California,  92120,  United States
      Loma Linda University Medical Center, Loma Linda,  California,  92354,  United States
      Pacific Coast Hematology/Oncology Medical Group, Fountain Valley,  California,  92708,  United States
      Pacific Hematology/Oncology, San Francisco,  California,  94115,  United States
      Southwest Cancer Care, Escondido,  California,  92025-4404,  United States
      Sutter Cancer Center, Sacramento,  California,  95816,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94143-0128,  United States
      University of California Davis Medical Center, Sacramento,  California,  95817,  United States
      University of California Los Angeles School of Medicine, Los Angeles,  California,  90095,  United States
      USC/Norris Comprehensive Cancer Center and Hospital, Los Angeles,  California,  90033-0804,  United States
Colorado
      Boulder Valley Oncology, LLP, Boulder,  Colorado,  80304,  United States
      Rocky Mountain Cancer Center, Englewood,  Colorado,  80110,  United States
      The Oncology Clinic, P.C., Colorado Springs,  Colorado,  80907,  United States
      US Oncology - Rocky Mountain Cancer Center, Littleton,  Colorado,  80120,  United States
      US Oncology, Rocky Mountain Cancer Centers, Lakewood,  Colorado,  80228,  United States
Connecticut
      Helen and Harry Gray Cancer Center, Hartford,  Connecticut,  06106,  United States
      Hematology Oncology, P.C., Stamford,  Connecticut,  06902,  United States
      Northwestern Connecticut Oncology-Hematology Associates, Torrington,  Connecticut,  06790,  United States
      St. Francis Hospital and Medical Center, Hartford,  Connecticut,  06105,  United States
      Yale Comprehensive Cancer Center, New Haven,  Connecticut,  06520-8028,  United States
District of Columbia
      Washington Cancer Institute, Washington,  District of Columbia,  20010,  United States
Florida
      Cancer Research Network Inc., Plantation,  Florida,  33324,  United States
      Cedars Medical Center, Miami,  Florida,  33136,  United States
      Center for Hematology-Oncology, Boca Raton,  Florida,  33486,  United States
      Comprehensive Cancer Care Specialists of Boca Raton, Boca Raton,  Florida,  33428,  United States
      Florida Cancer Specialists, Fort Myers,  Florida,  33901,  United States
      Florida Oncology Associates, Orange Park,  Florida,  32073,  United States
      Mount Sinai Comprehensive Cancer Center, Miami,  Florida,  33140,  United States
      Ocala Oncology Center, Ocala,  Florida,  34474,  United States
      Oncology Hematology Consultants, PA, Sarasota,  Florida,  34239,  United States
      Oncology Radiation Associates, Miami,  Florida,  33133,  United States
      US Oncology - Florida Community Cancer Center, Bradenton,  Florida,  34209,  United States
      Walt Disney Memorial Cancer Institute, Orlando,  Florida,  32803,  United States
Georgia
      American Medical Research Institute, Inc., Cumming,  Georgia,  30040,  United States
      Northwest Georgia Oncology Centers, P.C., Marietta,  Georgia,  30060,  United States
      Piedmont Hospital, Inc., Atlanta,  Georgia,  30309,  United States
Illinois
      Carle Cancer Center, Urbana,  Illinois,  61801,  United States
      Lutheran General Cancer Care Center, Park Ridge,  Illinois,  60068,  United States
      Midwest Clinical Research Group, Inc., Highland Park,  Illinois,  60035,  United States
      Rush North Shore Medical Center, Skokie,  Illinois,  60076,  United States
Indiana
      Oncology/Hematology Associates, Indianapolis,  Indiana,  46227,  United States
Kansas
      Oncology/Hematology Associates, Overland Park,  Kansas,  66210,  United States
      University of Kansas Medical Center, Kansas City,  Kansas,  66160-7357,  United States
Kentucky
      Consultants in Blood Disorders and Cancer, Louisville,  Kentucky,  40207,  United States
      Norton Healthcare Pavilion, Louisville,  Kentucky,  40202,  United States
Louisiana
      Louisiana Oncology Associates, Lafayette,  Louisiana,  70506,  United States
      Mary Bird Perkins Cancer Center, Baton Rouge,  Louisiana,  70809,  United States
      Ochsner Cancer Institute, New Orleans,  Louisiana,  70121,  United States
Maine
      Maine Center for Cancer Medicine and Blood Disorders, Scarborough,  Maine,  04074,  United States
Maryland
      Associates in Oncology and Hematology, Rockville,  Maryland,  20850,  United States
      Greater Baltimore Medical Center and Cancer Center, Baltimore,  Maryland,  21204,  United States
Massachusetts
      New England Hematology/Oncology Associates, P.C., Wellesley,  Massachusetts,  02181,  United States
      St. Elizabeth's Medical Center of Boston, Brighton,  Massachusetts,  02135,  United States
Michigan
      Henry Ford Hospital, Detroit,  Michigan,  48202,  United States
      Offices of R.H. Clark and J.A. Axelson, Jackson,  Michigan,  49201,  United States
      Oncology and Hematology, P.C., Kalamazoo,  Michigan,  49007,  United States
      Southfield Oncology Institute, Inc., Southfield,  Michigan,  48076,  United States
Minnesota
      Minnesota Oncology-Hematology, P.A., Minneapolis,  Minnesota,  55407,  United States
Missouri
      Ellis Fischel Cancer Center - Columbia, Columbia,  Missouri,  65203,  United States
      Midwest Oncology Consortium, Kansas City,  Missouri,  64111,  United States
      Missouri Cancer Care, P.C., St. Charles,  Missouri,  63301,  United States
      Oncology Hematology Associates of Kansas City, Kansas City,  Missouri,  64131,  United States
      St. John's Mercy Medical Center, Saint Louis,  Missouri,  63141,  United States
      Washington University Siteman Cancer Center, Saint Louis,  Missouri,  63110,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
Nevada
      University Medical Center - Las Vegas, Las Vegas,  Nevada,  89102-2386,  United States
      Veterans Affairs Medical Center - Reno, Reno,  Nevada,  89520,  United States
New Jersey
      Hackensack University Medical Center, Hackensack,  New Jersey,  07601,  United States
      Overlook Hospital, Summit,  New Jersey,  07902-0220,  United States
      Saint Clare's Hospital, Denville,  New Jersey,  07834,  United States
New Mexico
      Veterans Affairs Medical Center - Albuquerque, Albuquerque,  New Mexico,  87108-5138,  United States
New York
      Advanced Oncology Associates, Armonk,  New York,  10504,  United States
      Cancer Research of Long Island, Inc., Great Neck,  New York,  11022,  United States
      HemOnCare, P.C., Brooklyn,  New York,  11235,  United States
      Interlakes Oncology/Hematology PC, Rochester,  New York,  14623,  United States
      Milstein Hospital Building, New York,  New York,  10032,  United States
      New York Presbyterian Hospital - Cornell Campus, New York,  New York,  10021,  United States
      NYU School of Medicine's Kaplan Comprehensive Cancer Center, New York,  New York,  10016,  United States
      St. Luke's-Roosevelt Hospital, New York,  New York,  10019,  United States
      US Oncology, Rocky Mountain Cancer Center, Albany,  New York,  12203,  United States
      Veterans Affairs Medical Center - Albany, Albany,  New York,  12208,  United States
North Carolina
      Asheville Hematology and Oncology Associates, P.A., Asheville,  North Carolina,  28801,  United States
      Carolinas Medical Center, Charlotte,  North Carolina,  28232-2861,  United States
      CCOP - Southeast Cancer Control Consortium, Winston Salem,  North Carolina,  27104-4241,  United States
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
      N.W. Carolina Oncology & Hematology, P.A., Hickory,  North Carolina,  28603,  United States
      nTouch Research Corporation, Raleigh,  North Carolina,  27610,  United States
      Raleigh Hematology Oncology Associates, P.C., Raleigh,  North Carolina,  27607,  United States
      Raleigh Internal Medicine, Raleigh,  North Carolina,  27609,  United States
      Regional Hematology Oncology Associates, Durham,  North Carolina,  27704,  United States
Ohio
      Barrett Cancer Center, The University Hospital, Cincinnati,  Ohio,  45219,  United States
      Haematology-Oncology Associates, Inc., Toledo,  Ohio,  43623-4474,  United States
      Mid-Ohio Oncology/Hematology, Inc., Columbus,  Ohio,  43222,  United States
Oklahoma
      nTouch Research, Oklahoma City,  Oklahoma,  73109,  United States
      Oklahoma Oncology Inc., Tulsa,  Oklahoma,  74104,  United States
      University of Oklahoma Health Sciences Center, Oklahoma City,  Oklahoma,  73190,  United States
Oregon
      Kaiser Permanente - Portland, Portland,  Oregon,  97227,  United States
Pennsylvania
      Hematology/Oncology Associates of NE Pennsylvania, P.C., Scranton,  Pennsylvania,  18510,  United States
      Milton S. Hershey Medical Center, Hershey,  Pennsylvania,  17033-0850,  United States
      University of Pennsylvania Cancer Center, Philadelphia,  Pennsylvania,  19104-4283,  United States
South Carolina
      Palmetto Richland Memorial Hospital, Columbia,  South Carolina,  29203,  United States
      Spartanburg Regional Healthcare System, Spartanburg,  South Carolina,  29303,  United States
      Veterans Affairs Medical Center - Columbia, Columbia,  South Carolina,  20209,  United States
Tennessee
      Baptist Regional Cancer Center - Knoxville, Knoxville,  Tennessee,  37901,  United States
      Dial Research Associates, Brentwood,  Tennessee,  37027,  United States
      Sarah Cannon-Minnie Pearl Cancer Center, Nashville,  Tennessee,  37203,  United States
      University of Tennessee, Memphis, Memphis,  Tennessee,  38163,  United States
      University of Tennessee, Memphis Cancer Center, Memphis,  Tennessee,  38103,  United States
      Vanderbilt-Ingram Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Texas
      Scott and White Clinic, Temple,  Texas,  76508,  United States
      Texas Oncology, P.A., Dallas,  Texas,  75231,  United States
      Texas Oncology, P.A., Austin,  Texas,  78745,  United States
      US Oncology (Texas Oncology) PA, Houston,  Texas,  77030,  United States
      US Oncology, Texas Cancer Center, Denton,  Texas,  76205,  United States
Utah
      Intermountain Hematology/Oncology Associates, Inc., Salt Lake City,  Utah,  84124,  United States
Virginia
      Hematology & Oncology Associates of Virginia, Richmond,  Virginia,  23226,  United States
      Northern Virginia Oncology Group, P.C., Fairfax,  Virginia,  22031,  United States
Washington
      Madigan Army Medical Center, Tacoma,  Washington,  98431-5000,  United States
      Northwest Cancer Specialists, Vancouver,  Washington,  98664,  United States
      Swedish Cancer Institute, Seattle,  Washington,  98104,  United States
      Virginia Mason Medical Center, Seattle,  Washington,  98111,  United States
      Western Washington Oncology, Inc., Olympia,  Washington,  98502,  United States
Wisconsin
      Marshfield Clinic - Lakeland Center, Minocqua,  Wisconsin,  54548,  United States
      Medical College of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States
      Rhinelander Medical Center, Rhinelander,  Wisconsin,  54501,  United States

Study chairs or principal investigators

Beth Drena,  Study Chair,  Genentech   

Study ID Numbers:  CDR0000068496; GENENTECH-AVF2107g; UCLA-0008022
Record last reviewed:  February 2004
Last Updated:  October 13, 2004
Record first received:  March 3, 2001
ClinicalTrials.gov Identifier:  NCT00012233
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08