RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, irinotecan, and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining more than one drug with a monoclonal antibody may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective with or without cetuximab in treating metastatic adenocarcinoma (cancer) of the colon or rectum.

PURPOSE: Randomized phase III trial to compare the effectiveness of combining fluorouracil and leucovorin with either irinotecan or oxaliplatin with or without cetuximab in treating patients who have metastatic cancer of the colon or rectum.

Condition	Treatment or Intervention	Phase
adenocarcinoma of the colon adenocarcinoma of the rectum recurrent colon cancer recurrent rectal cancer stage IV colon cancer Stage IV rectal cancer	Drug: cetuximab  Drug: fluorouracil  Drug: irinotecan  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: Primary

• Compare the survival rate of patients with previously untreated metastatic adenocarcinoma of the colon or rectum treated with fluorouracil and leucovorin calcium with oxaliplatin or irinotecan and with or without cetuximab.

Secondary

• Determine the level of epidermal growth factor receptor (EGFR) expression in patients treated with these regimens.
• Determine whether expression of EGFR activity, markers of EGFR activity, and serum levels of insulin-like growth factor-1, C-peptide, and insulin-like growth factor binding protein 3 are independent predictors of response rate, time to tumor progression, and survival of patients treated with these regimens.
• Correlate specific germline polymorphisms related to chemotherapy metabolism and resistance with treatment-related toxicity, tumor response, time to tumor progression, and survival of patients treated with these regimens.
• Correlate expression of putative prognostic markers in the tumor with tumor response, time to tumor progression, and survival of patients treated with these regimens.
• Correlate diet, obesity, physical activity, and other lifestyle habits with treatment-related toxicity, progression-free survival, and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to prior adjuvant therapy (yes vs no) and prior pelvic radiotherapy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I (FOLFIRI): Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48 hours beginning on days 1, 15, 29, and 43.
• Arm II (FOLFIRI and cetuximab): Patients receive FOLFIRI as in arm I and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.
• Arm III (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48 hours beginning on days 1, 15, 29, and 43.
• Arm IV (FOLFOX and cetuximab): Patients receive FOLFOX as in arm III and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50. In all arms, courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed every 2 months for 2 years and then every 3 months for 3 years.

PROJECTED ACCRUAL: Approximately 2,200 patients (550 per treatment arm) will be accrued for this study within 4.6 years.

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic colorectal adenocarcinoma
• Primary site of disease in the large bowel as determined endoscopically, surgically, or radiologically
• Histologic or cytologic confirmation is not required for recurrent metastatic disease in patients with prior colorectal cancer treated with surgery unless either of the following criteria are met:
• More than 5 years have elapsed between the prior primary surgery and the development of metastatic disease
• Primary cancer was stage I
• Tumor tissue available for epidermal growth factor receptor (EGFR) status analysis
• No pleural effusion or ascites that causes grade 2 or greater dyspnea
• No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm^3
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• AST ≤ 5.0 times upper limit of normal (ULN)
• Albumin ≥ 2.5 g/dL
• No evidence of Gilbert's syndrome

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No unstable angina
• No congestive heart failure
• No prior myocardial infarction
• No prior stroke
• No other significant cardiac disease
• LVEF ≥ normal by echocardiogram or MUGA

Pulmonary

• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

Neurologic

• No uncontrolled seizure disorder
• No active neurological disease
• No symptomatic sensory peripheral neuropathy grade 2 or greater

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No predisposing uncontrolled colonic or small bowel disorder as evidenced by > 3 watery or soft stools daily at baseline*
• No known sensitivity to chimerized or murine antibodies, cetuximab or other EGFR inhibitors, or tyrosine kinase inhibitors
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix NOTE: *In patients without a colostomy or ileostomy; patients with a colostomy or ileostomy are eligible at the discretion of the investigator

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior biologic therapy for metastatic colorectal cancer
• No prior chimerized or murine antibodies
• No prior cetuximab
• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

• See Radiotherapy
• More than 12 months since prior chemotherapy
• No prior chemotherapy for metastatic colorectal cancer
• No prior irinotecan or oxaliplatin in the adjuvant or metastatic setting
• No more than 6 months or 4 courses of prior adjuvant chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• No prior endocrine therapy for metastatic colorectal cancer
• No concurrent hormonal therapy except the following:
• Steroids for adrenal failure
• Hormones administered for non-disease-related conditions (e.g., insulin for diabetes)
• Intermittent use of dexamethasone as an antiemetic

Radiotherapy

• More than 4 weeks since prior radiotherapy
• No prior radiotherapy for metastatic colorectal cancer
• No prior radiotherapy to more than 25% of bone marrow
• Prior standard adjuvant chemoradiotherapy for rectal cancer allowed
• Prior adjuvant radiotherapy with radiosensitizing chemotherapy allowed
• No concurrent palliative radiotherapy except whole brain radiotherapy for documented CNS disease

Surgery

• See Disease Characteristics
• More than 4 weeks since prior major surgery*
• More than 2 weeks since prior minor surgery* and recovered
• No prior surgery for metastatic colorectal cancer NOTE: *Insertion of a vascular device is not considered major or minor surgery

Other

• At least 4 weeks since prior itraconazole or ketoconazole
• No other prior treatment for metastatic colorectal cancer
• No prior EGFR inhibitors
• No prior tyrosine kinase inhibitors
• No other concurrent investigational agents
• No concurrent agents to minimize neurotoxicity of oxaliplatin (e.g., carbamazepine, magnesium, or calcium)

Alabama
      Northeast Alabama Regional Medical Center, Anniston,  Alabama,  36207,  United States
California
      Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center, Los Angeles,  California,  90048,  United States
      Naval Medical Center - San Diego, San Diego,  California,  92134-3202,  United States
      Rebecca and John Moores UCSD Cancer Center, La Jolla,  California,  92093-0658,  United States
      UCSF Comprehensive Cancer Center, San Francisco,  California,  94115,  United States
      Veterans Affairs Medical Center - San Diego, San Diego,  California,  92161,  United States
      Veterans Affairs Medical Center - San Francisco, San Francisco,  California,  94121,  United States
Delaware
      CCOP - Christiana Care Health Services, Newark,  Delaware,  19713,  United States
District of Columbia
      Lombardi Cancer Center at Georgetown University Medical Center, Washington,  District of Columbia,  20007,  United States
      Veterans Affairs Medical Center - Washington, DC, Washington,  District of Columbia,  20422,  United States
      Walter Reed Army Medical Center, Washington,  District of Columbia,  20307-5001,  United States
Florida
      Broward General Medical Center, Fort Lauderdale,  Florida,  33316,  United States
      CCOP - Mount Sinai Medical Center, Miami Beach,  Florida,  33140,  United States
      Florida Hospital Cancer Institute, Orlando,  Florida,  32804,  United States
      Memorial Regional Cancer Center at Memorial Regional Hospital, Hollywood,  Florida,  33021,  United States
      Palm Beach Cancer Institute, West Palm Beach,  Florida,  33401,  United States
Illinois
      CCOP - Evanston, Evanston,  Illinois,  60201,  United States
      CCOP - Illinois Oncology Research Association, Peoria,  Illinois,  61615-7828,  United States
      Louis A. Weiss Memorial Hospital, Chicago,  Illinois,  60640,  United States
      MBCCOP - University of Illinois at Chicago, Chicago,  Illinois,  60612,  United States
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637-1470,  United States
      Veterans Affairs Medical Center - Chicago (Westside Hospital), Chicago,  Illinois,  60612,  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
      Fort Wayne Medical Oncology and Hematology, Incorporated, Fort Wayne,  Indiana,  46885-5099,  United States
Iowa
      Holden Comprehensive Cancer Center at University of Iowa, Iowa City,  Iowa,  52242-1009,  United States
Kentucky
      Baptist Hospital East - Louisville, Louisville,  Kentucky,  40207,  United States
Maryland
      Greenebaum Cancer Center at University of Maryland Medical Center, Baltimore,  Maryland,  21201,  United States
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
      UMASS Memorial Cancer Center - University Campus, Worcester,  Massachusetts,  01655,  United States
Michigan
      Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph, Saint Joseph,  Michigan,  49085,  United States
Minnesota
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
      Veterans Affairs Medical Center - Minneapolis, Minneapolis,  Minnesota,  55417,  United States
Missouri
      CCOP - Kansas City, Kansas City,  Missouri,  64131,  United States
      Ellis Fischel Cancer Center at University of Missouri - Columbia, Columbia,  Missouri,  65203,  United States
      Missouri Baptist Cancer Center, Saint Louis,  Missouri,  63131,  United States
      Siteman Cancer Center at Barnes-Jewish Hospital, Saint Louis,  Missouri,  63110,  United States
      Veterans Affairs Medical Center - Columbia (Truman Memorial), Columbia,  Missouri,  65201,  United States
Nebraska
      UNMC Eppley Cancer Center at the University of Nebraska Medical Center, Omaha,  Nebraska,  68198-7680,  United States
Nevada
      CCOP - Southern Nevada Cancer Research Foundation, Las Vegas,  Nevada,  89106,  United States
      Veterans Affairs Medical Center - Las Vegas, Las Vegas,  Nevada,  89106,  United States
New Hampshire
      New Hampshire Oncology-Hematology, PA - Hooksett, Hooksett,  New Hampshire,  03106,  United States
      Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon,  New Hampshire,  03756-0002,  United States
New Jersey
      Cooper University Hospital, Camden,  New Jersey,  08103,  United States
New York
      CCOP - North Shore University Hospital, Manhasset,  New York,  11030,  United States
      CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C., East Syracuse,  New York,  13057,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
      Mount Sinai Medical Center, New York,  New York,  10029,  United States
      New York Weill Cornell Cancer Center at Cornell University, New York,  New York,  10021,  United States
      North Shore University Hospital, Manhasset,  New York,  11030,  United States
      Queens Cancer Center of Queens Hospital, Jamaica,  New York,  11432,  United States
      SUNY Upstate Medical University Hospital, Syracuse,  New York,  13210,  United States
      Veterans Affairs Medical Center - Buffalo, Buffalo,  New York,  14215,  United States
      Veterans Affairs Medical Center - Syracuse, Syracuse,  New York,  13210,  United States
North Carolina
      Cape Fear Valley Health System, Fayetteville,  North Carolina,  28302-2000,  United States
      CCOP - Southeast Cancer Control Consortium, Goldsboro,  North Carolina,  27534-9479,  United States
      Comprehensive Cancer Center at Wake Forest University, Winston Salem,  North Carolina,  27157-1082,  United States
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      FirstHealth Moore Regional Hospital, Pinehurst,  North Carolina,  28374,  United States
      Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill, Chapel Hill,  North Carolina,  27599-7295,  United States
      NorthEast Oncology Associates - Concord, Concord,  North Carolina,  28025,  United States
      Veterans Affairs Medical Center - Asheville, Asheville,  North Carolina,  28805,  United States
      Veterans Affairs Medical Center - Durham, Durham,  North Carolina,  27705,  United States
      Zimmer Cancer Center at New Hanover Regional Medical Center, Wilmington,  North Carolina,  28402-9025,  United States
Ohio
      Arthur G. James Cancer Hospital at Ohio State University, Columbus,  Ohio,  43210-1240,  United States
Oklahoma
      Oklahoma University Medical Center, Oklahoma City,  Oklahoma,  73104,  United States
Pennsylvania
      Western Pennsylvania Hospital, Pittsburgh,  Pennsylvania,  15224,  United States
Rhode Island
      Lifespan: The Miriam Hospital, Providence,  Rhode Island,  02906,  United States
Texas
      Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas,  Texas,  75390-8852,  United States
      Veterans Affairs Medical Center - Dallas, Dallas,  Texas,  75219,  United States
Vermont
      Vermont Cancer Center at University of Vermont, Burlington,  Vermont,  05401-3498,  United States
Virginia
      Martha Jefferson Hospital, Charlottesville,  Virginia,  22902,  United States
      MBCCOP - Massey Cancer Center, Richmond,  Virginia,  23298-0037,  United States
      Oncology and Hematology Associates of Southwest Virginia, Incorporated - Roanoke, Roanoke,  Virginia,  24014,  United States
      Virginia Oncology Associates - Norfolk, Norfolk,  Virginia,  23502,  United States
West Virginia
      St. Mary's Medical Center, Huntington,  West Virginia,  25701,  United States

Study chairs or principal investigators

Alan Paul Venook, MD,  Study Chair,  University of California, San Francisco   

Study ID Numbers:  CDR0000350016; CALGB-80203; NCT00077233
Record last reviewed:  February 2005
Last Updated:  February 9, 2005
Record first received:  February 10, 2004
ClinicalTrials.gov Identifier:  NCT00077233
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08