RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as 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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer.

PURPOSE: This randomized phase III trial is studying three different combination chemotherapy regimens with or without bevacizumab to compare how well they work in treating patients who have undergone surgery for stage II or stage III colon cancer.

Condition	Treatment or Intervention	Phase
stage II colon cancer stage III colon cancer	Drug: bevacizumab  Drug: capecitabine  Drug: fluorouracil  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: adjuvant therapy  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: growth factor antagonist therapy  Procedure: monoclonal antibody therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare disease-free survival of patients with high-risk stage II or stage III colon cancer treated with adjuvant oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX-4) vs bevacizumab and FOLFOX-4 vs bevacizumab, oxaliplatin, and capecitabine.

Secondary

• Compare overall survival of patients treated with these regimens.
• Compare the safety of these regimens in these patients.

Tertiary

• Compare the perceived convenience and satisfaction with chemotherapy in patients treated with these regimens.
• Compare medical care utilization in patients treated with these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to geographic region and disease stage (high-risk stage II vs stage III N1 vs stage III N2). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium (LV) IV over 2 hours and fluorouracil (5-FU) IV continuously over 22 hours on days 1 and 2. Treatment repeats every 14 days for a total of 12 courses.
• Arm II: Patients receive bevacizumab IV over 30-90 minutes on day 1 and oxaliplatin, LV, and 5-FU as in arm I. Treatment repeats every 14 days for a total of 12 courses. Patients then receive bevacizumab IV alone over 30 minutes on day 1. Treatment with bevacizumab repeats every 21 days for a total of 8 courses.
• Arm III: Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for a total of 8 courses. Patients then receive bevacizumab IV alone over 30 minutes on day 1. Treatment with bevacizumab repeats every 21 days for a total of 8 courses. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months for 4 years and then annually for 2 years.

PROJECTED ACCRUAL: A total of 3,450 patients (1,150 per treatment arm) will be accrued for this study within 23 months.

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed colon cancer, meeting 1 of the following stage criteria:
• High-risk stage II disease, as defined by 1 of the following criteria:
• T4 tumor
• Bowel obstruction or perforation
• Histological signs of vascular invasion (i.e., blood and lymphatic vessels) or perineural invasion
• Age < 50 years
• Sub-optimal surgery (< 12 lymph nodes analyzed)
• Stage III disease
• Tumor location ≥ 15 cm from the anal verge by endoscopy OR above the peritoneal reflection at surgery
• Not a candidate for neoadjuvant radiotherapy
• Has undergone curative surgery within the past 4-8 weeks
• No microscopic or macroscopic evidence of remaining tumor
• No evidence of metastatic disease (including presence of tumor cells in ascites)
• An isolated finding of cytokeratin-positive cells in the bone marrow is not considered evidence of metastatic disease
• Carcinoembryonic antigen ≤ 1.5 times upper limit of normal (ULN) after surgery
• No history or evidence of CNS disease (e.g., primary brain tumor or brain metastases) by physical exam

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 5 years

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL (transfusion allowed)
• No bleeding diathesis or coagulopathy

Hepatic

• INR ≤ 1.5
• PTT < 1.5 times ULN
• Bilirubin ≤ 1.5 times ULN
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN

Renal

• No proteinuria, defined as protein > 1 g by 24-hour urine collection
• Creatinine ≤ 1.5 times ULN OR
• Creatinine clearance > 50 mL/min

Cardiovascular

• No cerebrovascular accident within the past 6 months
• No myocardial infarction within the past year
• No uncontrolled hypertension while on chronic medication
• No unstable angina
• No New York Heart Association class II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No other clinically significant cardiovascular disease

Pulmonary

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

Gastrointestinal

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

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after study participation
• Willing to delay colostomy revision until ≥ 28 days after study completion
• No significant traumatic injury within the past 28 days
• No serious non-healing wound, ulcer, or bone fracture
• No other malignancy within the past 5 years except curatively treated basal cell skin cancer or carcinoma in situ of the cervix
• No seizure disorder that is not controlled by standard medical therapy
• No clinically significant psychiatric disability that would preclude giving informed consent or study participation
• No known peripheral neuropathy ≥ grade 1
• Absence of deep tendon reflexes as the sole neurologic abnormality does not render the patient ineligible
• No serious infection that is uncontrolled or requires treatment
• No known dihydropyrimidine dehydrogenase deficiency
• No known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies
• No known allergy to any of the study drugs or their excipients
• No metabolic dysfunction, physical examination finding, clinical laboratory finding, or other disease that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior antiangiogenic therapy for any malignancy
• No prior immunotherapy for colon cancer
• No concurrent active or passive immunotherapy for colon cancer

Chemotherapy

• No prior cytotoxic chemotherapy for colon cancer

Endocrine therapy

• No concurrent chronic corticosteroid treatment (≥ 10 mg/day of methylprednisolone or equivalent)
• Concurrent inhaled steroids allowed

Radiotherapy

• No prior radiotherapy for colon cancer

Surgery

• See Disease Characteristics
• More than 28 days since prior major surgical procedure or open biopsy
• No organ allograft requiring immunosuppressive therapy
• No concurrent major surgery

Other

• More than 10 days since prior and no concurrent full-dose oral or parenteral anticoagulants or therapeutic thrombolytic agents
• More than 28 days since prior investigational drugs or participation in another investigational study
• No concurrent chronic daily high-dose aspirin (> 325 mg/day)
• No concurrent nonsteroidal anti-inflammatory drugs known to inhibit platelet function at doses used to treat chronic inflammatory disease
• Concurrent cyclooxygenase-2 inhibitors allowed
• No concurrent sorivudine or brivudine
• No concurrent cold cap or iced mouth rinses
• No other concurrent cytotoxic therapy for colon cancer
• No other concurrent investigational therapy for colon cancer
• No concurrent participation in another investigational study

Please refer to this study by ClinicalTrials.gov identifier  NCT00112918

California
      Jonsson Comprehensive Cancer Center at UCLA, Los Angeles,  California,  90095-7187,  United States; Recruiting

Study chairs or principal investigators

Joel Randolph Hecht, MD,  Principal Investigator,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000427299; UCLA-0412086-01; ROCHE-BO17920A
Record last reviewed:  May 2005
Last Updated:  June 2, 2005
Record first received:  June 2, 2005
ClinicalTrials.gov Identifier:  NCT00112918
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-06-07