RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, leucovorin, and capecitabine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them in different combinations may kill more tumor cells. Monoclonal antibodies, such as bevacizumab (Avastin™), can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known which regimen is more effective in treating advanced colorectal cancer.

PURPOSE: Randomizedphase III trial to compare the effectiveness of oxaliplatin and bevacizumab combined with either fluorouracil and leucovorin or capecitabine in treating patients who have metastatic or recurrent colorectal cancer.

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

Further Study Details: 

OBJECTIVES:

• Compare the incidence of grade 3 and 4 toxic effects occurring within the first 12 weeks of treatment with 2 different schedules of oxaliplatin, bevacizumab (Avastin™), leucovorin calcium, and fluorouracil or with oxaliplatin, Avastin™, and capecitabine in patients with advanced colorectal cancer.
• Compare the overall response rate, progression-free survival, and time to treatment failure in patients treated with these regimens.
• Compare the composite toxicity of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive bevacizumab (Avastin™) IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil (5-FU) IV over 46 hours beginning on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive Avastin™ IV over 30-90 minutes and oxaliplatin IV over 2 hours on days 1 and 15 and leucovorin calcium IV over 10 minutes and 5-FU IV over 3 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive Avastin™ IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed at 1 month, every 3 months for at least 2 years, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 375 patients (125 per treatment arm) will be accrued for this study.

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum
• Metastatic or recurrent disease not amenable to potentially curative treatment
• At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
• Histological or cytological confirmation is required for a solitary target lesion
• No CNS metastases

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• SGPT and SGOT no greater than 3 times ULN

Renal

• Creatinine no greater than 1.5 times ULN
• Creatinine clearance at least 30 mL/min

Cardiovascular

• No myocardial infarction within the past 6 months
• No clinical evidence of congestive heart failure
• No unstable coronary artery disease

Pulmonary

• No interstitial pneumonia
• No extensive symptomatic fibrosis of the lungs

Gastrointestinal

• Able to tolerate oral medication
• No lack of physical integrity of the upper gastrointestinal tract
• No malabsorption syndrome
• No swallowing difficulties

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after study participation
• No other concurrent serious illness
• No uncontrolled infection
• No other concurrent malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix or any other cancer for which the patient has been off all therapy and in remission for at least 5 years
• No peripheral neuropathy
• No hypersensitivity to any of the study drugs or their ingredients
• No known dihydropyrimidine dehydrogenase deficiency
• No other medical or psychiatric disorder that would preclude giving informed consent or complying with study

PRIOR CONCURRENT THERAPY: Biologic therapy

• No concurrent prophylactic hematopoietic growth factor therapy
• No prior bevacizumab (Avastin™)

Chemotherapy

• At least 6 months since prior adjuvant fluorouracil, leucovorin calcium, and irinotecan
• No prior oxaliplatin
• No prior chemotherapy for metastatic or recurrent disease
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy unless for the control of bone pain

Surgery

• Recovered from prior surgery
• No prior organ allografts

Other

• More than 4 weeks since prior investigational drugs
• No concurrent iced mouth rinses for the prevention of stomatitis
• No concurrent cold cap alopecia prevention
• No concurrent pyridoxine
• No concurrent sorivudine or chemically-related analogues (e.g., brivudine)
• No concurrent chronic aspirin, nonsteroidal anti-inflammatory drugs, or warfarin

Alabama
      University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham,  Alabama,  35294-3300,  United States
Arizona
      Arizona Clinical Research Center, Tucson,  Arizona,  85712,  United States
California
      California Cancer Care, Inc., Greenbrae,  California,  94904-2007,  United States
      Cancer and Blood Institute of the Desert, Rancho Mirage,  California,  92270,  United States
      Valley Tumor Medical Group, Lancaster,  California,  93534,  United States
Colorado
      Rocky Mountain Cancer Centers - Midtown, Denver,  Colorado,  80218,  United States
Connecticut
      Northwestern Connecticut Oncology-Hematology Associates, Torrington,  Connecticut,  06790,  United States
District of Columbia
      Lombardi Cancer Center at Georgetown University Medical Center, Washington,  District of Columbia,  20007,  United States
Florida
      Florida Cancer Specialists, Fort Myers,  Florida,  33901,  United States
      Florida Oncology Associates, Jacksonville,  Florida,  32207,  United States
      Hematology and Oncology Consultants, P.A., Orlando,  Florida,  32804,  United States
      Hematology Oncology Associates of theTreasure Coast - Port St. Lucie, Port St. Lucie,  Florida,  34952,  United States
      Lynn Regional Cancer Center West, Boca Raton,  Florida,  33428,  United States
      Palm Beach Cancer Institute, West Palm Beach,  Florida,  33401,  United States
Georgia
      Peachtree Hematology and Oncology Consultants, P.C., Atlanta,  Georgia,  30309,  United States
Idaho
      North Idaho Cancer Center, Coeur D Alene,  Idaho,  83814,  United States
Illinois
      Lutheran General Cancer Care Center, Park Ridge,  Illinois,  60068-1270,  United States
      Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago,  Illinois,  60611,  United States
      Saint Anthony Medical Center, Rockford,  Illinois,  61108,  United States
      West Suburban Center for Cancer Care, River Forest,  Illinois,  60305,  United States
Indiana
      CCOP - Northern Indiana CR Consortium, South Bend,  Indiana,  46601,  United States
Iowa
      Cedar Rapids Oncology Associates, Cedar Rapids,  Iowa,  52403-1206,  United States
Kansas
      CCOP - Wichita, Wichita,  Kansas,  67214-3882,  United States
Maryland
      Greater Baltimore Medical Center and Cancer Center, Baltimore,  Maryland,  21204,  United States
Mississippi
      Jackson Oncology Associates, PLLC, Jackson,  Mississippi,  39202,  United States
Missouri
      Veterans Affairs Medical Center - Kansas City, Kansas City,  Missouri,  64128,  United States
Montana
      Deaconess Billings Clinic Cancer Center, Billings,  Montana,  59107-5100,  United States
New Jersey
      Cooper Cancer Institute at Cooper University Hospital, Voorhees,  New Jersey,  08043,  United States
New York
      Advanced Oncology Associates, Armonk,  New York,  10504,  United States
      Arena Oncology Associates, Great Neck,  New York,  11021,  United States
      New York Medical College, Valhalla,  New York,  10595,  United States
      New York University Medical Center, New York,  New York,  10016,  United States
      North Shore Hematology/Oncology Associates, P.C., East Setauket,  New York,  11733,  United States
      St. Vincents Comprehensive Cancer Center, New York,  New York,  10011,  United States
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      Physicians East - Quadrangle, Greenville,  North Carolina,  27834,  United States
      Raleigh Hematology/Oncology Associates, P.A. - Wake Practice, Raleigh,  North Carolina,  27609-7300,  United States
      Southeastern Medical Oncology Center, Goldsboro,  North Carolina,  27534,  United States
Ohio
      Hematology Oncology Consultants Inc, Columbus,  Ohio,  43235,  United States
Oregon
      Hematology/Oncology of Salem, Salem,  Oregon,  97301,  United States
Pennsylvania
      Hillman Cancer Center at University of Pittsburgh Cancer Institute, Pittsburgh,  Pennsylvania,  15232,  United States
      Pennsylvania Oncology Hematology Associates, Philadelphia,  Pennsylvania,  19106,  United States
South Carolina
      Charleston Hematology-Oncology, P.A., Charleston,  South Carolina,  29403,  United States
Tennessee
      McCleod Cancer and Blood Center, Johnson City,  Tennessee,  37604,  United States
      Memphis Cancer Center, Memphis,  Tennessee,  38119,  United States
      Sarah Cannon Cancer Center at Centennial Medical Center, Nashville,  Tennessee,  37203,  United States
      West Clinic, Memphis,  Tennessee,  38120,  United States
Texas
      Center for Cancer Prevention and Care at Scott and White Clinic, Temple,  Texas,  76508,  United States
      Lone Star Oncology, Austin,  Texas,  78759,  United States
      Medical City Dallas Hospital, Dallas,  Texas,  75230,  United States
      South Texas Oncology and Hematology, San Antonio,  Texas,  78207,  United States
Wisconsin
      Medical Consultants, Milwaukee,  Wisconsin,  53215-3690,  United States

Study chairs or principal investigators

Richard Alan Gams, MD,  Study Chair,  Prologue Research International   
Lauri Welles, MD,  Sanofi-Synthelabo   

Study ID Numbers:  CDR0000304771; PROLOGUE-SANOFI-ARD5099; SANOFI-ARD5099
Record last reviewed:  June 2004
Last Updated:  October 13, 2004
Record first received:  June 5, 2003
ClinicalTrials.gov Identifier:  NCT00062426
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08