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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00096278
First received: November 9, 2004
Last updated: May 16, 2014
Last verified: July 2013
  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. 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.


Condition Intervention Phase
Adenocarcinoma of the Colon
Stage IIA Colon Cancer
Stage IIB Colon Cancer
Stage IIC Colon Cancer
Stage IIIA Colon Cancer
Stage IIIB Colon Cancer
Stage IIIC Colon Cancer
Drug: oxaliplatin
Drug: leucovorin calcium
Drug: fluorouracil
Biological: bevacizumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
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:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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


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, 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
Study Completion Date: December 2012
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (mFOLFOX6)
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.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Experimental: Arm II (bevacizumab, mFOLFOX6)
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.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging disease-free survival (DFS).

SECONDARY OBJECTIVES:

I. To compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging survival (S).

TERTIARY OBJECTIVES:

I. To assess the persistence of proteinuria following the discontinuation of bevacizumab.

II. To correlate the development of proteinuria with clinical sequelae. III. To evaluate the risk factors for development of proteinuria. IV. To determine the effect of discontinuation of bevacizumab on hypertension. V. To estimate the incidence of delayed vascular events such as myocardia infarction, CNS ischemia, and thrombosis in patients receiving chemotherapy + bevacizumab.

VI. To assess the effect of bevacizumab on ovarian function in premenopausal women.

VII. To assess the incidence rate of immunogenicity and examine post-treatment serum levels of bevacizumab in patients receiving bevacizumab.

OUTLINE: This is a randomized, multicenter study. 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.

  Eligibility

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

Inclusion Criteria:

  • Patients must consent to be in the study and must have signed and dated an IRB approved consent form conforming to federal and institutional guidelines
  • Randomization must occur during the three-week interval beginning on postoperative day 29 and ending on postoperative day 50
  • The distal extent of the tumor must be >= 12 cm from the anal verge on endoscopy; if the patient is not a candidate for endoscopy, then the distal extent of the tumor must be >= 12 cm from the anal verge as determined by surgical examination
  • The patient must have had an en bloc complete gross resection of tumor (curative resection) by open laparotomy or laparoscopically-assisted colectomy; patients who have had a two-stage surgical procedure, to first provide a decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible
  • Patients must have histologically confirmed adenocarcinoma of the colon that meets one of the criteria below:

    • Stage II carcinoma (T3,4 N0 M0); the tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues (T3); or directly invades other organs or structures, and/or perforates visceral peritoneum (T4)
    • Stage III carcinoma (any T N1,2 M0); the tumor has invaded to any depth, with involvement of regional lymph nodes
  • Patients with T4 tumors that have involved an adjacent structure (e.g., bladder, small intestine, ovary, etc.) by direct extension from the primary tumor are eligible if all of the following conditions are met:

    • All or a portion of the adjacent structure was removed en bloc with the primary tumor
    • In the opinion of the surgeon, all grossly visible tumor was completely resected ("curative resection")
    • Histologic evaluation by the pathologist confirms the margins of the resected specimen are not involved by malignant cells; and
    • Local radiation therapy will not be utilized
  • Patients with more than one synchronous primary colon tumor are eligible; (staging classification will be based on the more advanced primary tumor)
  • Patients must have an ECOG performance status of 0 or 1
  • At the time of randomization, postoperative absolute granulocyte count (AGC) must be >= 1500/mm^3 (or < 1500/mm^3, if in the opinion of the investigator, this represents an ethnic or racial variation of normal)
  • At the time of randomization, the postoperative platelet count must be >= 100,000/mm^3
  • Bilirubin must be =< ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin
  • Alkaline phosphatase must be < 2.5 x ULN for the lab
  • AST must be < 1.5 x ULN for the lab

    • If AST is > ULN, serologic testing for hepatitis B and C must be performed and results must be negative
  • Serum creatinine =< 1.5 x ULN for the lab
  • Urine protein/creatinine (UPC) ratio of < 1.0; patients with a UPC ratio >= 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1 gm of protein in the 24-hour urine collection in order to participate in the study
  • Patients with prior malignancies, including colorectal cancers, are eligible if they have been disease-free for >= 5 years and are deemed by their physician to be at low risk for recurrence; patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization

Exclusion Criteria:

  • Patients < 18 years old
  • Colon tumor other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, etc
  • Rectal tumors, i.e. a tumor located < 12 cm from the anal verge on endoscopy, or by surgical exam if the patient is not a candidate for endoscopy
  • Isolated, distant, or non-contiguous intra-abdominal metastases, even if resected
  • Any systemic or radiation therapy initiated for this malignancy
  • Any significant bleeding that is not related to the primary colon tumor within 6 months before study entry
  • Serious or non-healing wound, skin ulcers, or bone fracture
  • Gastroduodenal ulcer(s) determined by endoscopy to be active
  • Invasive procedures defined as follows:

    • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
    • Anticipation of need for major surgical procedures during the course of the study
    • Core biopsy or other minor procedure, excluding placement of a vascular access device, within 7 days prior to randomization
  • Uncontrolled blood pressure defined as > 150/90 mmHg
  • History of TIA or CVA
  • History of arterial thrombotic event within 12 months before study entry
  • Symptomatic peripheral vascular disease
  • PT/INR > 1.5, unless the patient is on therapeutic doses of warfarin. If so, the following criteria must be met for enrollment:

    • The subject must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin
    • The subject must not have active bleeding or a pathological condition that is associated with a high-risk of bleeding
  • Concomitant halogenated antiviral agents
  • Clinically significant peripheral neuropathy at the time of randomization (defined in the NCI Common Terminology Criteria for Adverse Events Version 3.0 [CTCAE v3.0] as grade 2 or greater neurosensory or neuromotor toxicity)
  • Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study therapy drugs; specifically excluded are the following cardiac conditions:

    • New York Heart Association Class III or IV cardiac disease
    • History of myocardial infarction within 12 months before study entry
    • Unstable angina within 12 months before study entry; and
    • Symptomatic arrhythmia
  • History of chronic or persistent viral hepatitis or other chronic liver disease
  • Pregnancy or lactation at the time of proposed randomization; eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods during study therapy and for at least 3 months after the completion of bevacizumab
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, Pennsylvania
National Surgical Adjuvant Breast and Bowel Project
Pittsburgh, Pennsylvania, United States, 15212-5234
Sponsors and Collaborators
Investigators
Principal Investigator: Carmen Allegra NSABP Foundation Inc
  More Information

No publications provided by National Cancer Institute (NCI)

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, U10CA012027
Study First Received: November 9, 2004
Results First Received: October 31, 2012
Last Updated: May 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Colonic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Antibodies
Fluorouracil
Antibodies, Monoclonal
Bevacizumab
Oxaliplatin
Leucovorin
Levoleucovorin
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 30, 2014