Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II or Stage III Colon Cancer
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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.
Condition | Intervention | Phase |
---|---|---|
Colorectal Cancer |
Biological: bevacizumab Drug: 5-fluorouracil Drug: leucovorin Drug: oxaliplatin |
Phase 3 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
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 |
- Disease-free Survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]Where events are defined as recurrence, second primary cancer, or death from any cause
- Survival as Assessed by Death From Any Cause [ Time Frame: Every 6 months for 4 years and then every 12 months until death from any cause ] [ Designated as safety issue: No ]
- Proteinuria After Completion of Bevacizumab [ Time Frame: For Groups 1 and 2 at the end of every 3 cycles of chemotherapy plus or minus bevacizumab; for Group 2 patients, every 6 weeks for 6 months. If UPC ratio is greater than or equal to 1.0 at the end of therapy then test every 3 months for 12 months ] [ Designated as safety issue: Yes ]
- Proteinuria With Clinical Sequelae [ Time Frame: For Groups 1 and 2 at the end of every 3 cycles of chemotherapy plus or minus bevacizumab; for Group 2 patients, every 6 weeks for 6 months. If UPC ratio is greater than or equal to 1.0 at the end of therapy then test every 3 months for 12 months ] [ Designated as safety issue: Yes ]
- The Risk Factors for Development of Proteinuria [ Time Frame: For Groups 1 and 2 at the end of every 3 cycles of chemotherapy plus or minus bevacizumab; for Group 2 patients, every 6 weeks for 6 months. If UPC ratio is greater than or equal to 1.0 at the end of therapy then test every 3 months for 12 months ] [ Designated as safety issue: Yes ]
- As Measured by Blood Pressure and Antihypertensive Medication Hypertension [ Time Frame: Group 2, every 3 months for one year post treatment ] [ Designated as safety issue: Yes ]
- Delayed Vascular Events Such as Myocardial Infarction, Central Nervous System (CNS) Ischemia, and Thrombosis in Patients Receiving Chemotherapy + Bevacizumab [ Time Frame: Events measured regularly during chemotherapy and bevacizumab therapy ] [ Designated as safety issue: Yes ]
- Ovarian Function in Premenopausal Women as Measured by Serum Ovarian Function Test [ Time Frame: Group 2: Measured pre-therapy and then every 6 months for 2 years following randomization ] [ Designated as safety issue: Yes ]
- Bevacizumab Immunogenicity and Post-treatment Serum Levels of Bevacizumab in Patients Receiving Bevacizumab [ Time Frame: Group 2: Pre-therapy, every 2 weeks during chemotherapy/bevacizumab therapy, every 6 weeks during bevacizumab therapy and at 3 and 6 months after completion of bevacizumab therapy ] [ Designated as safety issue: Yes ]
Enrollment: | 2710 |
Study Start Date: | September 2004 |
Estimated Study Completion Date: | March 2014 |
Primary Completion Date: | March 2009 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
---|---|
Active Comparator: Arm 1: Oxaliplatin + Leucovorin + 5-Fluorouracil
Oxaliplatin + Leucovorin + 5-Fluorouracil
|
Drug: 5-fluorouracil
5-FU 400 mg/m2 IV bolus Day 1 every 14 days for 12 cycles and 5-FU 2400 mg/m2 by continuous IV infusion over 46 hours (Day 1 and Day 2) every 14 days for 12 cycles
Drug: leucovorin
leucovorin 400 mg/m2 IV Day 1 every 14 days for 12 cycles
Drug: oxaliplatin
Oxaliplatin 85 mg/m2 IV day 1 every 14 days for 12 cycles
|
Experimental: Arm 2: Oxaliplatin + Leucovorin + 5-Fluorouracil + Bevacizumab
Oxaliplatin + Leucovorin + 5-Fluorouracil + Bevacizumab
|
Biological: bevacizumab
bevacizumab 5 mg/kg IV day 1 every 14 days for 1 year
Drug: 5-fluorouracil
5-FU 400 mg/m2 IV bolus Day 1 every 14 days for 12 cycles and 5-FU 2400 mg/m2 by continuous IV infusion over 46 hours (Day 1 and Day 2) every 14 days for 12 cycles
Drug: leucovorin
leucovorin 400 mg/m2 IV Day 1 every 14 days for 12 cycles
Drug: oxaliplatin
Oxaliplatin 85 mg/m2 IV day 1 every 14 days for 12 cycles
|
Detailed Description:
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, Central Nervous System (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.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | 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
- Eastern Cooperative Oncology Group (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
Aspartate Aminotransferase (AST) < 1.5 times ULN
- If AST > normal, serologic testing for hepatitis B and C is required and the results must be negative
No Prothrombin Time and International Normalized Ratio (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
Show 570 Study Locations
Principal Investigator: | Norman Wolmark, MD | NSABP Foundation, Inc. |
Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | National Cancer Institute (NCI) |
ClinicalTrials.gov Identifier: | NCT00096278 History of Changes |
Other Study ID Numbers: | NCI-2012-03017, NSABP C-08 |
Study First Received: | November 9, 2004 |
Results First Received: | October 31, 2012 |
Last Updated: | January 2, 2013 |
Health Authority: | United States: Food and Drug Administration |
Keywords provided by National Cancer Institute (NCI):
adenocarcinoma of the colon stage II colon cancer stage III colon cancer |
Additional relevant MeSH terms:
Colonic Neoplasms Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases Fluorouracil Oxaliplatin Bevacizumab |
Leucovorin Levoleucovorin Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antimetabolites, Antineoplastic Antineoplastic Agents Therapeutic Uses Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Vitamin B Complex Vitamins Micronutrients Growth Substances |
ClinicalTrials.gov processed this record on February 28, 2013