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NCT00265850

PHASE3

Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer

Sponsor: Alliance for Clinical Trials in Oncology

View on ClinicalTrials.gov

Summary

PURPOSE: This randomized phase III trial is studying cetuximab and/or bevacizumab when given together with combination chemotherapy to compare how well they work in treating patients with metastatic colorectal cancer. RATIONALE: Monoclonal antibodies, such as cetuximab and 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. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, leucovorin, oxaliplatin, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibodies together with combination chemotherapy may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with cetuximab and/or bevacizumab in treating patients with colorectal cancer.

Official title: A Phase III Trial of Irinotecan / 5-FU / Leucovorin or Oxaliplatin / 5-FU/ Leucovorin With Bevacizumab, or Cetuximab (C225), or With the Combination of Bevacizumab and Cetuximab for Patients With Untreated Metastatic Adenocarcinoma of the Colon or Rectum

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

2334

Start Date

2005-11

Completion Date

2018-01

Last Updated

2026-08-07

Healthy Volunteers

Conditions

Colorectal Cancer

Interventions

BIOLOGICAL

bevacizumab

Given IV

BIOLOGICAL

cetuximab

Given IV

DRUG

FOLFOX or

Patients receive oxaliplatin 85 mg/m\^2 IV infused over two hours followed by leucovorin 400 mg/m\^2 IV over 2 hours followed by 5-FU 400 mg/m\^2 IV bolus, then 2400 mg/m\^2 continuous IV infusion over 46-48 hours

DRUG

FOLFIRI

Patients receive irinotecan 180 mg/m\^2 IV infused over 90 minutes followed by leucovorin 400 mg/m\^2 IV over 2 hours followed by 5-FU 400 mg/m\^2 IV bolus following leucovorin then 2400 mg/m\^2 continuous IV infusion over 46-48 hours.

1. Locally Advanced or Metastatic Colorectal Cancer 1. Eligible patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have either locally advanced (unresectable) or metastatic disease. Patients with resected primary tumors who have documented metastases are eligible. Documentation of residual disease by CT scan or surgeon's notes is required for all patients, and histologic confirmation of metastases is strongly encouraged. 2. Patients with a history of colorectal cancer treatment by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless: * Either an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease or * The primary cancer was stage I. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature or source of apparent metastases. 3. At the time of randomization, the intent of this treatment must be indicated palliative or neoadjuvant chemotherapy with the potential for resection of all sites of metastatic disease. 2. Only patients with a wildtype K-ras gene as determined by the laboratory at the SWOG Solid Tumor Repository or by a local CLIA-certified laboratory are eligible. Patients with a mutation in the K-ras gene are ineligible. All patients must have available for analysis of K-ras status at least one H and E slide and one paraffin block of the previously resected primary colorectal tumor and/or a tumor deposit. For patients registered and randomized based on local CLIA-certified laboratory results, SWOG analysis will be confirmatory only. 3. Prior Treatment 1. No prior systemic treatment for advanced or metastatic colorectal cancer is allowed. Prior regional chemotherapy (eg, hepatic arterial infusion) is also not allowed. * Patients may have received prior adjuvant chemotherapy that included fluorouracil alone or in combination with fluorouracil and oxaliplatin or irinotecan (no more than 6 months); or radiation with radiosensitizing chemotherapy. * The last course of adjuvant chemotherapy must have concluded \> 12 months prior to colorectal cancer recurrence. * Patients may have received neoadjuvant chemo-radiation with capecitabine or 5-fluorouracil. * Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to randomization. * No prior exposure to any tyrosine kinase inhibitors or other agents (including protein products, monoclonal antibodies, antisense, etc.) that target VEGF or EGF receptors is allowed. * No prior treatment with bevacizumab or cetuximab. 2. Patients may not have had prior radiotherapy to greater than 25% of bone marrow. (Standard adjuvant rectal cancer chemoradiation will not exclude patient from protocol entry.) Radiation must have concluded ≥ 4 weeks prior to randomization. 3. Patients should have completed any major surgery ≥ 4 weeks from randomization. Patients must have completed any minor surgery ≥ 2 weeks prior to randomization. Patients must have fully recovered from the procedure. (Insertion of a vascular access device is not considered major or minor surgery.) 4. No previous or concurrent malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years. 5. For patients who are to receive FOLFIRI: No evidence of Gilbert's Syndrome or of homozygosity for the UGT1A1\*28 allele. 1. Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome would include a prior finding of an isolated elevation of indirect bilirubin. 2. UGT1A1 genotyping is not required on this study. However, patients known to be homozygous for the UGT1A1\*28 allele are not to receive FOLFIRI for this study. Patients with Gilbert's Syndrome or who are found to be homozygous for the UGT1A1 allele who will receive FOLFOX are eligible. 6. No sensory peripheral neuropathy of ≥ grade 2 at baseline for patients who are to receive FOLFOX. 7. No known central nervous system metastases or carcinomatous meningitis. 8. No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung. 9. No pleural effusion or ascites that causes ≥ grade 2 dyspnea. 10. No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of \> 3 watery or soft stools daily in patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy may entered at investigator discretion. 11. Patients must not have an uncontrolled seizure disorder, or active neurological disease. 12. No current congestive heart failure (New York Heart Association Class II, III or IV) 13. Patients with history of hypertension must be well controlled ( \< 160/90) on a regimen of anti-hypertensive therapy. 14. Patients on full-dose anticoagulation (eg, warfarin) are eligible provided that both of the following criteria are met: 1. The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or be on a stable dose of low molecular weight heparin. 2. The patient has no active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices). 15. Patients receiving anti-platelet agents are eligible. In addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible. 16. No significant history of bleeding events or GI perforation: 1. Patients with a history of significant bleeding episodes (eg, hemoptysis, upper or lower GI bleeding ) within 6 months of randomization are not eligible unless the source of bleeding has been resected. 2. Patients with a history of GI perforation within 12 months of randomization are not eligible. 17. No arterial thrombotic events within 6 months before randomization, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI). Patients with clinically significantly peripheral artery disease (eg, claudication on less than one block) or any other arterial thrombotic event are also ineligible. 18. No serious or non-healing wound, ulcer or bone fracture 19. Patients with known hypersensitivity to Chinese hamster ovary cell products or to recombinant human or murine antibodies are not eligible. 20. Non-pregnant and not nursing: 1. Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to randomization. 2. DNA alkylating agents are known to be teratogenic, and the effects of irinotecan, oxaliplatin, 5-FU, bevacizumab, and cetuximab on a developing fetus at the recommended therapeutic doses are unknown. 3. Women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. 4. Postmenopausal is defined as amenorrhea ≥ 12 consecutive months or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL. 5. Women of child-bearing potential also include women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (eg, vasectomy), should be considered to be of child bearing potential. 21. ECOG Performance Status of 0-1 22. Age ≥ 18 years 23. Required Initial Laboratory Values: 1. Granulocytes ≥ 1500 µL 2. Hemoglobin ≥ 9.0 grams/dL (patient may be transfused to meet this criterion) 3. Platelet count ≥ 100,000/µL 4. Creatinine ≤ 1.5 x Upper limits of normal 5. Bilirubin ≤ 1.5 mg/dL 6. Albumin ≥ 2.5 g/dL 7. Urinalysis ≤ 1 + protein\* * \*Patients discovered to have ≥ 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate \< 1 g of protein/24 hour or have a UPC \< 1.0 to allow participation in the study.

Locations (683)

Providence Cancer Center at Providence Hospital

Mobile, Alabama, United States

Alaska Regional Hospital Cancer Center

Anchorage, Alaska, United States

Providence Cancer Center

Anchorage, Alaska, United States

Hembree Mercy Cancer Center at St. Edward Mercy Medical Center

Fort Smith, Arkansas, United States

NEA Medical Center - Stadium Boulevard

Jonesboro, Arkansas, United States

Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center

Burbank, California, United States

East Bay Radiation Oncology Center

Castro Valley, California, United States

Valley Medical Oncology Consultants - Castro Valley

Castro Valley, California, United States

North Bay Cancer Center

Fairfield, California, United States

Kaiser Permanente - Fremont

Fremont, California, United States

Valley Medical Oncology

Fremont, California, United States

Glendale Memorial Hospital Comprehensive Cancer Center

Glendale, California, United States

California Cancer Care, Incorporated - Greenbrae

Greenbrae, California, United States

Kaiser Permanente Medical Center - Hayward

Hayward, California, United States

Veterans Affairs Medical Center - Loma Linda (Pettis)

Loma Linda, California, United States

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, United States

Contra Costa Regional Medical Center

Martinez, California, United States

Tibotec Therapeutics - Division of Ortho Biotech Products, LP

Marysville, California, United States

Camino Medical Group - Treatment Center

Mountain View, California, United States

El Camino Hospital Cancer Center

Mountain View, California, United States

Alta Bates Summit Medical Center - Summit Campus

Oakland, California, United States

Bay Area Breast Surgeons, Incorporated

Oakland, California, United States

CCOP - Bay Area Tumor Institute

Oakland, California, United States

Larry G Strieff MD Medical Corporation

Oakland, California, United States

Tom K Lee, Incorporated

Oakland, California, United States

Kaiser Permanente Medical Center - Oakland

Oakland, California, United States

St. Joseph Hospital Regional Cancer Center - Orange

Orange, California, United States

Desert Regional Medical Center Comprehensive Cancer Center

Palm Springs, California, United States

Palo Alto Medical Foundation

Palo Alto, California, United States

Valley Medical Oncology Consultants - Pleasanton

Pleasanton, California, United States

Kaiser Permanente Medical Center - Redwood City

Redwood City, California, United States

Kaiser Permanente Medical Center - Richmond

Richmond, California, United States

Kaiser Permanente Medical Center - Roseville

Roseville, California, United States

University of California Davis Cancer Center

Sacramento, California, United States

South Sacramento Kaiser-Permanente Medical Center

Sacramento, California, United States

Kaiser Permanente Medical Center - Sacramento

Sacramento, California, United States

Kaiser Permanente Medical Office -Vandever Medical Office

San Diego, California, United States

Naval Medical Center - San Diego

San Diego, California, United States

San Francisco General Hospital Medical Center

San Francisco, California, United States

Kaiser Permanente Medical Center - San Francisco Geary Campus

San Francisco, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

Kaiser Permanente Medical Center - Santa Teresa

San Jose, California, United States

Kaiser Foundation Hospital - San Rafael

San Rafael, California, United States

Kaiser Permanente Medical Center - Santa Clara Kiely Campus

Santa Clara, California, United States

Kaiser Permanente Medical Center - Santa Rosa

Santa Rosa, California, United States

Kaiser Permanente Medical Center - South San Francisco

South San Francisco, California, United States

Saint Helena Hospital

St. Helena, California, United States

Kaiser Permanente Medical Facility - Stockton

Stockton, California, United States

Tahoe Forest Cancer Center

Truckee, California, United States

Kaiser Permanente Medical Center - Vallejo

Vallejo, California, United States

Kaiser Permanente Medical Center - Walnut Creek

Walnut Creek, California, United States

San Luis Valley Regional Medical Center

Alamosa, Colorado, United States

Aurora Presbyterian Hospital

Aurora, Colorado, United States

University of Colorado Cancer Center at UC Health Sciences Center

Aurora, Colorado, United States

Boulder Community Hospital

Boulder, Colorado, United States

Memorial Hospital Cancer Center - Colorado Springs

Colorado Springs, Colorado, United States

Penrose Cancer Center at Penrose Hospital

Colorado Springs, Colorado, United States

Denver Health Medical Center

Denver, Colorado, United States

St. Anthony Central Hospital

Denver, Colorado, United States

Kaiser Permanente - Denver

Denver, Colorado, United States

Porter Adventist Hospital

Denver, Colorado, United States

Presbyterian - St. Luke's Medical Center

Denver, Colorado, United States

St. Joseph Hospital

Denver, Colorado, United States

Rose Medical Center

Denver, Colorado, United States

Veterans Affairs Medical Center - Denver

Denver, Colorado, United States

CCOP - Colorado Cancer Research Program

Denver, Colorado, United States

Shaw Regional Cancer Center

Edwards, Colorado, United States

Swedish Medical Center

Englewood, Colorado, United States

Poudre Valley Hospital

Fort Collins, Colorado, United States

Front Range Cancer Specialists

Fort Collins, Colorado, United States

Valley View Hospital Cancer Center

Glenwood Springs, Colorado, United States

St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center

Grand Junction, Colorado, United States

North Colorado Medical Center

Greeley, Colorado, United States

Kaiser Permanente - Lafayette

Lafayette, Colorado, United States

Littleton Adventist Hospital

Littleton, Colorado, United States

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Hope Cancer Care Center at Longmont United Hospital

Longmont, Colorado, United States

McKee Medical Center

Loveland, Colorado, United States

Montrose Memorial Hospital Cancer Center

Montrose, Colorado, United States

Parker Adventist Hospital

Parker, Colorado, United States

St. Mary - Corwin Regional Medical Center

Pueblo, Colorado, United States

North Suburban Medical Center

Thornton, Colorado, United States

Exempla Lutheran Medical Center

Wheat Ridge, Colorado, United States

Bendheim Cancer Center at Greenwich Hospital

Greenwich, Connecticut, United States

Helen and Harry Gray Cancer Center at Hartford Hospital

Hartford, Connecticut, United States

Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States

Middlesex Hospital Cancer Center

Middletown, Connecticut, United States

George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus

New Britain, Connecticut, United States

Eastern Connecticut Hematology and Oncology Associates

Norwich, Connecticut, United States

Kent General Hospital

Dover, Delaware, United States

Tunnell Cancer Center at Beebe Medical Center

Lewes, Delaware, United States

CCOP - Christiana Care Health Services

Newark, Delaware, United States

Washington Cancer Institute at Washington Hospital Center

Washington D.C., District of Columbia, United States

Sibley Memorial Hospital

Washington D.C., District of Columbia, United States

Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus

Boca Raton, Florida, United States

Memorial Cancer Institute at Memorial Regional Hospital

Hollywood, Florida, United States

Lakeland Regional Cancer Center at Lakeland Regional Medical Center

Lakeland, Florida, United States

Florida Hospital Cancer Institute at Florida Hospital Orlando

Orlando, Florida, United States

Sacred Heart Cancer Center at Sacred Heart Hospital

Pensacola, Florida, United States

Sacred Heart Medical Oncology

Pensacola, Florida, United States

Phoebe Cancer Center at Phoebe Putney Memorial Hospital

Albany, Georgia, United States

Northeast Georgia Cancer Care, LLC - Medical Oncology

Athens, Georgia, United States

Piedmont Hospital

Atlanta, Georgia, United States

Northside Hospital Cancer Center

Atlanta, Georgia, United States

Saint Joseph's Hospital of Atlanta

Atlanta, Georgia, United States

CCOP - Atlanta Regional

Atlanta, Georgia, United States

MBCCOP - Medical College of Georgia Cancer Center

Augusta, Georgia, United States

WellStar Cobb Hospital

Austell, Georgia, United States

John B. Amos Cancer Center

Columbus, Georgia, United States

Charles B. Eberhart Cancer Center at DeKalb Medical Center

Decatur, Georgia, United States

Veterans Affairs Medical Center - Atlanta (Decatur)

Decatur, Georgia, United States

Dublin Hematology and Oncology Care

Dublin, Georgia, United States

Piedmont Fayette Hospital

Fayetteville, Georgia, United States

Northeast Georgia Medical Center

Gainesville, Georgia, United States

Gwinnett Medical Center

Lawrenceville, Georgia, United States

Medical Center of Central Georgia

Macon, Georgia, United States

Kennestone Cancer Center at Wellstar Kennestone Hospital

Marietta, Georgia, United States

Southern Regional Medical Center

Riverdale, Georgia, United States

Harbin Clinic Cancer Center - Medical Oncology

Rome, Georgia, United States

Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center

Savannah, Georgia, United States

Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler

Savannah, Georgia, United States

Pearlman Comprehensive Cancer Center at South Georgia Medical Center

Valdosta, Georgia, United States

Cancer Research Center of Hawaii