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Oxaliplatin, Leucovorin, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer
This study has been suspended.
First Received: September 20, 2005   Last Updated: May 1, 2009   History of Changes
Sponsors and Collaborators: Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00217737
  Purpose

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, 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 remaining tumor cells or prevent the cancer from coming back. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone or observation only in treating colon cancer.

PURPOSE: This randomized phase III trial is studying oxaliplatin, leucovorin, fluorouracil, and bevacizumab to see how well they work compared to oxaliplatin, leucovorin, and fluorouracil or observation only in treating patients who have undergone surgery for stage II colon cancer.


Condition Intervention Phase
Colorectal Cancer
Biological: bevacizumab
Drug: fluorouracil
Drug: leucovorin calcium
Drug: oxaliplatin
Procedure: observation
Phase III

Study Type: Interventional
Study Design: Treatment, Randomized, Active Control
Official Title: A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin Versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Stage II Colon Cancer at High Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular Markers

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Disease-free survival at 3 years [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
  • Correlation of tumor biologic characteristics with survival [ Designated as safety issue: No ]

Estimated Enrollment: 3610
Study Start Date: August 2005
Estimated Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm I: Active Comparator
Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV bolus followed by fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses.
Drug: fluorouracil
Given IV
Drug: leucovorin calcium
Given IV
Drug: oxaliplatin
Given IV
Arm II: Experimental
Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses.
Biological: bevacizumab
Given IV
Drug: fluorouracil
Given IV
Drug: leucovorin calcium
Given IV
Drug: oxaliplatin
Given IV
Arm III: No Intervention
Patients undergo observation only.
Procedure: observation
No intervention

Detailed Description:

OBJECTIVES:

Primary

  • Compare the 3-year disease-free survival of patients with resected stage II colon cancer at high risk for recurrence treated with oxaliplatin, leucovorin calcium, and fluorouracil with vs without bevacizumab.

Secondary

  • Compare the overall survival of patients treated with these regimens.
  • Compare the toxicity profiles of these regimens in these patients.
  • Correlate tumor biologic characteristics with survival of patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are stratified according to disease stage (IIA vs IIB) and microsatellite stability (MSS) (stable vs low-grade instability [MSI-L]). Patients with disease that is at high risk for microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosome 18q are randomized to 1 of 2 treatment arms (arms I and II). Patients with disease that is at low risk for MSI and 18q LOH are assigned to arm III.

  • Arm I: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV bolus followed by fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses in the absence of disease progression or unacceptable toxicity.
  • Arm III: Patients undergo observation only. Patients are followed every 3 months for 1-2 years, every 6 months for 3 years, and then annually for up to 10 years from study entry.

PROJECTED ACCRUAL: A total of 3,610 patients will be accrued for this study within 5.8 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

    • Stage II disease (T3-4, N0, M0)

      • At least 8 lymph nodes must have been evaluated
  • Meets 1 of the following criteria:

    • High risk for microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosome 18q

      • Microsatellite stable (MSS) with 18q LOH
      • MSI-low grade (MSI-L) with 18q LOH
    • Low risk for MSI and 18q LOH

      • MSS with retention of 18q alleles
      • MSI-L with retention of 18q alleles
      • MSI-high grade (MSI-H) with retention of 18q alleles
      • MSI-H without retention of 18q alleles
      • MSI-H with 18q status uninformative
  • Distal extent of tumor must be ≥ 12 cm from the anal verge by endoscopy or surgical examination

    • If tumor is located beyond sigmoid colon and centimeter distance is unavailable, include anatomic region of the colon (e.g., right colon, transverse colon, hepatic flexure, descending colon, or cecum)
  • Has undergone surgical resection of the tumor between the past 28-60 days

    • Must have had a complete resection (R0 resection)
  • No history of isolated, distant, or noncontiguous intra-abdominal metastases
  • Patients with synchronous tumors or appendiceal tumors are ineligible
  • Hereditary non-polyposis colorectal cancer allowed
  • Paraffin-embedded tumor specimen (one with normal mucosa and one from the resection tumor) available

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Performance status

  • ECOG 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Absolute granulocyte count ≥ 1,500/mm^3*
  • Platelet count ≥ 100,000/mm^3*
  • No significant bleeding unrelated to tumor within the past 6 months* NOTE: *For patients with high-risk disease only

Hepatic

  • Bilirubin normal (unless due to Gilbert's disease or similar syndrome)*
  • Alkaline phosphatase (AP) < 2.5 times upper limit of normal (ULN)*
  • AST < 1.5 times ULN*
  • PT INR > 1.5* allowed provided the following criteria are met:

    • Patient is on full-dose anticoagulants
    • INR in range (usually 2-3) on a stable dose of warfarin or low molecular weight heparin
    • No active bleeding or pathological condition associated with a high risk of bleeding unrelated to primary colon tumor
  • No systemic hepatic disease* NOTE: *For patients with high-risk disease only

Renal

  • Creatinine ≤ 1.5 times ULN*
  • Urine protein:creatinine ratio < 1.0* OR
  • Urine protein < 1 gm on 24-hour urine collection*
  • No systemic renal disease* NOTE: *For patients with high-risk disease only

Cardiovascular

  • History of hypertension allowed provided blood pressure < 150/90 mm Hg while on a stable regimen of anti-hypertensive therapy*
  • No New York Heart Association class III or IV cardiac disease*
  • No symptomatic arrhythmia*
  • No history of transient ischemic attack*
  • No history of cerebrovascular accident*
  • No symptomatic peripheral vascular disease*
  • No arterial thromboembolic events within the past 12 months*
  • No unstable angina within the past 12 months*
  • No myocardial infarction within the past 12 months*
  • No other systemic cardiovascular disease* NOTE: *For patients with high-risk disease only

Other

  • Not pregnant or nursing*
  • Negative pregnancy test*
  • Fertile patients must use effective contraception during and for 3 months after completion of study treatment*
  • No active gastroduodenal ulcer by endoscopy*
  • No complete obstruction or perforation of the bowel
  • No history of inflammatory bowel disease
  • No prior or concurrent malignancy except for nonmelanoma skin cancer, carcinoma in situ of the cervix, breast cancer in situ, treated non-pelvic cancer from which the patient has been disease-free for > 5 years, or history of breast cancer (without evidence of disease) and remain on hormonal therapy for > 5 years
  • No other nonmalignant systemic disease that would preclude study compliance*
  • No psychiatric or addictive disorder or other condition that would preclude study participation*
  • No serious or non-healing wound, skin ulcer, or bone fracture*
  • No peripheral neuropathy ≥ grade 2*
  • No significant traumatic injury within the past 4 weeks*
  • No known allergy to platinum compounds NOTE: *For patients with high-risk disease only

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Not specified

Chemotherapy

  • Not specified

Endocrine therapy

  • Not specified

Radiotherapy

  • No prior radiotherapy for this cancer

Surgery

  • See Disease Characteristics
  • More than 28 days since prior major surgery or open biopsy*
  • More than 7 days since prior core biopsy or other minor procedure except placement of a vascular access device* NOTE: *For patients with high-risk disease only

Other

  • No prior systemic therapy for this cancer NOTE: *For patients with high-risk disease only
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00217737

  Show 736 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Study Chair: Al B. Benson, MD, FACP Robert H. Lurie Cancer Center
Investigator: Peter J. O'Dwyer, MD, BCh University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: ECOG Group Chair's Office ( Robert L. Comis )
Study ID Numbers: CDR0000443410, ECOG-E5202
Study First Received: September 20, 2005
Last Updated: May 1, 2009
ClinicalTrials.gov Identifier: NCT00217737     History of Changes
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
adenocarcinoma of the colon
stage II colon cancer

Study placed in the following topic categories:
Antimetabolites
Immunologic Factors
Gastrointestinal Diseases
Colonic Diseases
Leucovorin
Bevacizumab
Rectal Diseases
Oxaliplatin
Vitamins
Micronutrients
Digestive System Neoplasms
Vitamin B Complex
Trace Elements
Folinic Acid
Intestinal Diseases
Immunosuppressive Agents
Angiogenesis Inhibitors
Intestinal Neoplasms
Recurrence
Calcium, Dietary
Digestive System Diseases
Fluorouracil
Gastrointestinal Neoplasms
Adenocarcinoma
Colonic Neoplasms
Colorectal Neoplasms

Additional relevant MeSH terms:
Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Gastrointestinal Diseases
Antineoplastic Agents
Colonic Diseases
Physiological Effects of Drugs
Leucovorin
Bevacizumab
Rectal Diseases
Oxaliplatin
Neoplasms by Site
Vitamins
Therapeutic Uses
Growth Inhibitors
Angiogenesis Modulating Agents
Micronutrients
Vitamin B Complex
Digestive System Neoplasms
Growth Substances
Intestinal Diseases
Angiogenesis Inhibitors
Immunosuppressive Agents
Intestinal Neoplasms
Pharmacologic Actions
Neoplasms
Digestive System Diseases
Fluorouracil
Gastrointestinal Neoplasms

ClinicalTrials.gov processed this record on July 06, 2009