Official Title: “A Phase III Clinical Trial Comparing Infusional 5-Fluorouracil (5-FU), Leucovorin, and Oxaliplatin (mFOLFOX6) Every Two Weeks With Bevacizumab to the Same Regimen Without Bevacizumab for the Treatment of Patients With Resected Stages II and III Carcinoma of the Colon”

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop tumor cells from dividing so they stop growing or die.

Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Bevacizumab may also stop the growth of tumor cells by stopping blood flow to the tumor. Giving chemotherapy together with bevacizumab may kill more tumor cells. It is not yet known whether treatment with oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating patients who have undergone surgery for colon cancer.

PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin, and fluorouracil together with bevacizumab to see how well it works compared to oxaliplatin, leucovorin, and fluorouracil alone in treating patients who have undergone surgery for stage II or stage III colon cancer.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

OBJECTIVES:

Primary - Compare disease-free survival of patients with resected stage II or III adenocarcinoma of the colon treated with adjuvant chemotherapy comprising fluorouracil, leucovorin calcium, and oxaliplatin with vs without bevacizumab.

Secondary - Compare overall survival of patients treated with these regimens.

Tertiary - Determine the persistence of proteinuria after completion of bevacizumab in patients treated with bevacizumab. - Correlate the development of proteinuria with clinical sequelae in patients treated with bevacizumab. - Determine risk factors for development of proteinuria in patients treated with bevacizumab. - Determine the effect of discontinuing bevacizumab on hypertension in these patients. - Determine the incidence of delayed vascular events (e.g., myocardial infarction, CNS ischemia, and thrombosis) in patients treated with chemotherapy in combination with bevacizumab. - Determine the effect of this drug on ovarian function in premenopausal women. - Determine the incidence rate of immunogenicity and serum levels of bevacizumab in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center and number of positive lymph nodes (0 vs 1-3 vs > 3). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive adjuvant chemotherapy comprising concurrent oxaliplatin and leucovorin calcium IV over 2 hours on day 1. Patients also receive adjuvant fluorouracil IV over 2-4 minutes on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity. - Arm II: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive adjuvant oxaliplatin, leucovorin calcium, and fluorouracil as in arm I.

Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of adjuvant chemotherapy, patients continue to receive bevacizumab alone every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,632 patients (1,316 per treatment arm) will be accrued for this study within 2.5 years.

Intervention(s) in this Clinical Trial

• Biological: bevacizumab
• Drug: FOLFOX regimen
• Drug: fluorouracil
• Drug: leucovorin calcium
• Drug: oxaliplatin
• Procedure: adjuvant therapy

Primary Measures

• Disease-free survival as assessed by recurrence, second primary cancer, or death from any cause every 6 months for 4 years
  • Safety Issue?: No

Secondary Measures

• Survival as assessed by death from any cause after 2 years
  • Safety Issue?: No
• Treatment related mortality as assessed by CTCAE version 3.0 at 6 months
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon, meeting 1 of the following stage criteria:
• Stage II disease (T3 or 4, N0, M0)
• Stage III disease (any T, N1 or 2, M0)
• No rectal tumors
• Distal extent of tumor ≥ 12 cm from the anal verge by endoscopy or surgical examination
• T4 tumors involving an adjacent structure (e.g., bladder, small intestine, or ovary) by direct extension from the primary tumor are eligible provided the following criteria are met:
• All or a portion of the adjacent structure was removed en bloc with the primary tumor
• All grossly visible tumor was completely resected (i.e., curative resection) in the opinion of the surgeon
• Margins of the resected specimen not involved with malignant cells by pathology
• Not planning local radiotherapy
• En bloc complete gross resection of tumor by open laparotomy or laparoscopically-assisted colectomy within the past 29-50 days
• Two-stage surgical procedure allowed (i.e., decompressive colostomy followed by definitive surgical resection)
• Patients with > 1 synchronous primary colon tumor are eligible
• Disease staging based on more advanced primary tumor
• No isolated, distant, or non-contiguous intra-abdominal metastases, even if resected

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Performance status
• ECOG 0-1
• Life expectancy
• At least 5 years
• Hematopoietic
• Absolute granulocyte count ≥ 1,500/mm^3 (unless it represents an ethnic or racial variation of normal)
• Postoperative platelet count ≥ 100,000/mm^3
• No significant bleeding unrelated to the primary colon tumor within the past 6 months
• Hepatic
• Bilirubin ≤ upper limit of normal (ULN) (unless due to slow conjugation of bilirubin caused by Gilbert's disease or a similar syndrome)
• Alkaline phosphatase < 2.5 times ULN
• AST < 1.5 times ULN
• If AST > normal, serologic testing for hepatitis B and C is required and the results must be negative
• No PT/INR > 1.5 unless patient is on full-dose anticoagulants AND the following criteria are met:
• INR 2-3 on a stable dose of warfarin
• No active bleeding
• No pathological condition associated with a high risk of bleeding
• No hepatic disease that would preclude study participation
• No history of viral hepatitis or other chronic liver disease
• Renal
• Serum creatinine ≤ 1.5 times ULN
• Urine protein/creatinine ratio < 1.0 OR
• < 1 g of protein on 24-hour urine collection
• No renal disease that would preclude study participation
• Cardiovascular
• No uncontrolled blood pressure, defined as > 150/90 mm Hg
• No cardiovascular disease that would preclude study participation, including any of the following:
• New York Heart Association class III or IV myocardial disease
• Myocardial infarction within the past 12 months
• Unstable angina within the past 12 months
• Symptomatic arrhythmia
• No history of transient ischemic attack or cerebrovascular accident
• No arterial thrombotic event within the past 12 months
• No symptomatic peripheral vascular disease
• Other
• No other malignancy within the past 5 years except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum
• Must be at low risk of recurrence from any prior malignancy
• No serious or non-healing wound, skin ulcer, or bone fracture
• No active gastroduodenal ulcer by endoscopy
• No clinically significant peripheral neuropathy (i.e., neurosensory or neuromotor toxicity ≥ grade 2)
• No significant traumatic injury within the past 4 weeks
• No other nonmalignant systemic disease that would preclude study participation
• No psychiatric or addictive disorder or other condition that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Patients randomized to receive bevacizumab must use effective contraception during and for 3 months after study treatment

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• No concurrent prophylactic growth factors
• No concurrent biological response modifiers
• Chemotherapy
• Not specified
• Endocrine therapy
• Not specified
• Radiotherapy
• See Disease Characteristics
• No prior radiotherapy for this malignancy
• No concurrent radiotherapy for this malignancy
• Surgery
• See Disease Characteristics
• Recovered from prior surgery
• More than 4 weeks since prior major surgery or open biopsy
• More than 7 days since prior core biopsy or other minor surgery (except placement of a vascular access device)
• No concurrent or anticipated concurrent major surgery
• Other
• No prior systemic therapy for this malignancy
• No concurrent halogenated antiviral agents (e.g., sorivudine)
• No other concurrent investigational drugs
• No other concurrent antineoplastic agents

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Surgical Adjuvant Breast and Bowel Project (NSABP)

Overall Clinical Trial Officials and Contacts

Carmen J. Allegra, MD Study Chair Network for Medical Communication and Research  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00096278

Study ID Number: CDR0000390343

ClinicalTrials.gov Identifier: NCT00096278

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database

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