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

Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed18 and overNCI, OtherCDR0000455161
CALGB-C80405, SWOG-C80405, C80405, NCT00265850

Trial Description

Summary

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.

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.

Further Study Information

OBJECTIVES:

Primary

  • Compare overall survival of patients with previously untreated metastatic colorectal cancer treated with cetuximab and/or bevacizumab in combination with either oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) OR irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI). (Arm III [cetuximab and bevacizumab in combination with FOLFOX or FOLFIRI] closed to accrual as of 09/10/2009)

Secondary

  • Compare response, progression-free survival, time to treatment failure, and duration of response in patients with unresectable disease treated with these regimens.
  • Compare toxicity and 60-day survival of patients with unresectable disease treated with these regimens.
  • Determine whether patients with unresectable disease become eligible for surgical resection after treatment with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to physician-selected chemotherapy (oxaliplatin, leucovorin calcium, and fluorouracil [FOLFOX] vs irinotecan hydrochloride, leucovorin calcium, or fluorouracil [FOLFIRI]), prior adjuvant chemotherapy (yes vs no), and prior pelvic radiotherapy (yes vs no). Patients are randomized to 1 of 3 treatment arms. (Arm III closed to accrual as of 09/10/2009)

  • Arm I: Patients receive oxaliplatin IV over 2 hours or irinotecan hydrochloride IV over 30-90 minutes; leucovorin calcium IV over 2 hours; fluorouracil IV continuously over 46-48 hours; and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.
  • Arm II: Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.
  • Arm III (closed to accrual as of 09/10/2009): Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, fluorouracil, and bevacizumab as in arm I. Patients also receive cetuximab as in arm II.

In all arms, treatment repeats every 56 days for at least 2 courses in the absence of disease progression, unacceptable toxicity, or planned surgery with curative intent.

For patients whom elective surgery is contemplated, bevacizumab must be discontinued for at least 8 weeks before surgery and may not be resumed for at least 4 weeks after surgery. Patients who undergo complete resection of metastatic disease are removed from study.

After completion of study treatment, patients are followed up every 2 months for 5 years and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 2,900 patients will be accrued for this study.

Eligibility Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
  • Locally advanced (unresectable) or metastatic disease
  • Patients with resected primary tumors who have documented metastases are eligible
  • Separate histological or cytological confirmation is not required from patients with a history of colorectal cancer (previously treated by surgical resection) who have now developed radiological or clinical evidence of metastatic disease, unless 1 of the following is true:
  • An interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease
  • The primary cancer was stage I
  • Patient must have a wildtype K-ras gene determined by the SWOG Solid Tumor Repository laboratory or by local CLIA-certified laboratory
  • Patients with a mutation in the K-ras gene not allowed
  • The intent of this treatment must be indicated as follows:
  • Palliative or neoadjuvant treatment with the potential for resection of all sites of metastatic disease
  • At least 1 paraffin block of previously resected primary tumor or tumor deposit available
  • Patients must have a wildtype K-ras gene
  • No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Performance status

  • ECOG 0-1

Life expectancy

  • Not specified

Hematopoietic

  • Granulocyte count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
  • No history of significant bleeding episodes (e.g., hemoptysis or upper or lower gastrointestinal bleeding) within the past 6 months unless the source of bleeding has been resected

Hepatic

  • Bilirubin ≤ 1.5 mg/dL
  • Albumin ≥ 2.5 g/dL
  • No evidence of Gilbert's syndrome for patients assigned to receive FOLFIRI chemotherapy
  • Gilbert's syndrome allowed for patients assigned to receive FOLFOX chemotherapy

Renal

  • Creatinine ≤ 1.5 times upper limit of normal
  • Protein < 1+ by urinalysis
  • Protein < 1 g by 24-hour urine collection for patients with protein ≥ 2+ by urinalysis

Cardiovascular

  • No arterial thromboembolic events within the past 6 months, including any of the following:
  • Myocardial infarction
  • Transient ischemic attack
  • Cerebrovascular accident
  • Unstable angina or angina requiring surgical or medical intervention
  • No uncontrolled hypertension (i.e., blood pressure ≥ 160/90 on a regimen of antihypertensive therapy)
  • No New York Heart Association class II-IV congestive heart failure
  • No clinically significant peripheral artery disease (i.e., claudication on less than 1 block)

Pulmonary

  • No interstitial pneumonia
  • No extensive or symptomatic interstitial fibrosis of the lung
  • No pleural effusion or ascites that causes ≥ grade 2 dyspnea

Gastrointestinal

  • No gastrointestinal perforation within past year
  • No uncontrolled, predisposing colonic or small bowel disorder (i.e., > 3 watery or soft stools daily for patients without a colostomy or ileostomy)
  • Patients with a colostomy or ileostomy are eligible at the discretion of the investigator

Neurologic

  • No sensory peripheral neuropathy ≥ grade 2 for patients assigned to receive FOLFOX chemotherapy
  • No uncontrolled seizure disorder
  • No active neurological disease

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for at least 2-6 months after completion of study treatment
  • No serious nonhealing wound, ulcer, or bone fracture
  • No known hypersensitivity to Chinese hamster ovary cell products or recombinant human or murine antibodies
  • 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • No prior agents that target vascular endothelial growth factor (VEGF) or EGF receptors including protein products, monoclonal antibodies, or antisense therapies
  • No prior bevacizumab or cetuximab
  • No concurrent prophylactic filgrastim (G-CSF), pegfilgrastim, or sargramostim (GM-CSF)

Chemotherapy

  • See Radiotherapy
  • More than 12 months since prior adjuvant chemotherapy (≤ 6 months in duration) that included fluorouracil alone or in combination with oxaliplatin or irinotecan hydrochloride
  • No prior regional chemotherapy (e.g., hepatic arterial infusion)
  • No other concurrent chemotherapy

Endocrine therapy

  • No concurrent hormonal therapy except steroids for adrenal failure, hormones for noncancer-related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic

Radiotherapy

  • Prior radiotherapy with radiosensitizing chemotherapy allowed
  • Prior standard adjuvant chemoradiotherapy for rectal cancer allowed
  • At least 4 weeks since prior radiotherapy
  • No prior radiotherapy to > 25% of bone marrow
  • No concurrent palliative radiotherapy except whole brain irradiation for documented CNS disease

Surgery

  • See Disease Characteristics
  • At least 4 weeks since prior major surgery
  • At least 2 weeks since prior minor surgery
  • Insertion of a vascular access device is not considered a prior surgery
  • Recovered from all prior surgery

Other

  • At least 4 weeks since prior itraconazole or ketoconazole
  • No prior tyrosine kinase inhibitor therapy
  • No prior systemic treatment for advanced or metastatic colorectal cancer
  • No concurrent aprepitant
  • Concurrent full-dose anticoagulation (i.e., warfarin) allowed provided all of the following criteria are met:
  • In-range INR (usually 2-3) on a stable dose of oral anticoagulant or stable dose of low molecular weight heparin
  • No active bleeding
  • No pathological condition with a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • Concurrent antiplatelet agents allowed
  • Concurrent daily prophylactic aspirin or anticoagulation for atrial fibrillation allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Cancer and Leukemia Group B

National Cancer Institute

Southwest Oncology Group

Alan Paul VenookStudy Chair

Charles D. BlankeStudy Chair

Trial Sites

U.S.A.
Illinois
  Alton
 Saint Anthony's Hospital at Saint Anthony's Health Center
 Bethany G. Sleckman Ph: 913-948-5588
  Mount Vernon
 Good Samaritan Regional Health Center
 Bethany G. Sleckman Ph: 913-948-5588
Louisiana
  Mansfield
 DeSoto Regional Hospital
 Glenn M. Mills Ph: 318-813-1412
  Monroe
 Louisiana State University Health Sciences Center - Monroe
 Glenn M. Mills Ph: 318-813-1412
  Shreveport
 Feist-Weiller Cancer Center at Louisiana State University Health Sciences
 Glenn M. Mills Ph: 318-813-1412
 Highland Clinic
 Glenn M. Mills Ph: 318-813-1412
Maine
  Lewiston
 Central Maine Comprehensive Cancer Center at Central Maine Medical Center
 Nicholette Erickson Ph: 207-795-8250
  Email: benderli@cmhc.org
Massachusetts
  Gloucester
 Addison Gilbert Hospital
 Angus P. McIntyre Ph: 978-283-4000ext559
Minnesota
  Fergus Falls
 Lake Region Healthcare Corporation-Cancer Care
 Preston D. Steen Ph: 701-234-6161
Missouri
  Cape Girardeau
 Saint Francis Medical Center
 Bethany G. Sleckman Ph: 913-948-5588
  Saint Louis
 CCOP - St. Louis-Cape Girardeau
 Bethany G. Sleckman Ph: 913-948-5588
 David C. Pratt Cancer Center at St. John's Mercy
 Bethany G. Sleckman Ph: 913-948-5588
 Mercy Clinic St. Louis Cancer and Breast Institute
 Bethany G. Sleckman Ph: 913-948-5588
Nevada
  Reno
 Renown Institute for Cancer at Renown Regional Medical Center
 Steven A. Schiff Ph: 775-982-4400
New Hampshire
  Nashua
 Foundation Medical Partners
 S. G Rao Ph: 603-577-3200
  Email: fmpclinicaltrials@snhmc.org
Ohio
  Beachwood
 Cleveland Clinic Taussig Cancer Center
 Anjali S Advani Ph: 866-223-8100
  Cleveland
 Cleveland Clinic Cancer Center at Fairview Hospital
 Anjali S Advani Ph: 866-223-8100
  Independence
 Cleveland Clinic Taussig Cancer Center
 Anjali S Advani Ph: 866-223-8100
Oklahoma
  Tulsa
 Natalie Warren Bryant Cancer Center at St. Francis Hospital
 Joseph P. Lynch Ph: 918-494-2200
Pennsylvania
  Williamsport
 Susquehanna Cancer Center at Divine Providence Hospital
 Warren L Robinson Ph: 800-598-4282
South Dakota
  Aberdeen
 Conklin Regional Cancer Center
 Richard J. Conklin Ph: 605-622-5613
Utah
  Salt Lake City
 Huntsman Cancer Institute at University of Utah
 John R. Weis Ph: 801-581-4477
  Email: clinical.trials@hci.utah.edu
Wisconsin
  Sheboygan
 Vince Lombardi Cancer Clinic - Sheboygan
 Dhimant R. Patel Ph: 800-252-2990

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00265850
ClinicalTrials.gov processed this data on October 17, 2013

Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials. Questions and comments regarding the presented information should be directed to ClinicalTrials.gov.

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