Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II or Stage III Colon Cancer - Full Text View

Sponsor:	National Surgical Adjuvant Breast and Bowel Project (NSABP)
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	National Surgical Adjuvant Breast and Bowel Project (NSABP)
ClinicalTrials.gov Identifier:	NCT00096278

Purpose

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 calcium Drug: oxaliplatin	Phase III

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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Colorectal Cancer High Blood Pressure

Drug Information available for: Fluorouracil Leucovorin Citrovorum factor Oxaliplatin Bevacizumab Leucovorin Calcium Folinic acid calcium salt pentahydrate

U.S. FDA Resources

Further study details as provided by National Surgical Adjuvant Breast and Bowel Project (NSABP):

Primary Outcome Measures:

Disease-free survival as assessed by recurrence, second primary cancer, or death from any cause [ Time Frame: Every 6 months for 4 years and then every 12 months until recurrence, second primary cancer, or death from any cause ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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, 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: Group 1 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 calcium 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: Group 2 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 calcium 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

Arms

Assigned Interventions

Active Comparator: Group 1

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 calcium

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: Group 2

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 calcium

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, 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00096278

Show 570 Study Locations

Sponsors and Collaborators

National Surgical Adjuvant Breast and Bowel Project (NSABP)

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Norman Wolmark, MD

NSABP Foundation, Inc.

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Featured trial article This link exits the ClinicalTrials.gov site

Publications:

Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer. J Clin Oncol. 2009 May 4; [Epub ahead of print]

Allegra CJ, Yothers G, O'Connell MJ, et al.: Initial safety report of NSABP C-08, a randomized phase III study of modified 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer. [Abstract] J Clin Oncol 26 (Suppl 15): A-4006, 2008.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yothers G, Sargent DJ, Wolmark N, Goldberg RM, O'Connell MJ, Benedetti JK, Saltz LB, Dignam JJ, Blackstock AW; ACCENT Collaborative Group. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst. 2011 Oct 19;103(20):1498-506. Epub 2011 Oct 12.

Responsible Party:	National Surgical Adjuvant Breast and Bowel Project (NSABP)
ClinicalTrials.gov Identifier:	NCT00096278 History of Changes
Other Study ID Numbers:	NSABP C-08, NSABP C-08
Study First Received:	November 9, 2004
Last Updated:	September 20, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Surgical Adjuvant Breast and Bowel Project (NSABP):

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 09, 2012