Bevacizumab and Oxaliplatin Combined With Irinotecan or Leucovorin and Fluorouracil in Treating Patients With Metastatic or Recurrent Colorectal Cancer

The recruitment status of this study is unknown because the information has not been verified recently.
Verified April 2012 by National Cancer Institute (NCI).
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00098787
First received: December 8, 2004
Last updated: July 18, 2012
Last verified: April 2012
  Purpose

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, irinotecan, 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 colorectal cancer by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may be a better way to block tumor growth. Studying the amount of an enzyme found in the tumor may help doctors plan the best treatment.

PURPOSE: This randomized phase II trial is studying giving bevacizumab, oxaliplatin, and irinotecan or giving bevacizumab, oxaliplatin, leucovorin, and fluorouracil in treating patients with metastatic or recurrent colorectal cancer.


Condition Intervention Phase
Colorectal Cancer
Biological: bevacizumab
Drug: fluorouracil
Drug: irinotecan hydrochloride
Drug: leucovorin calcium
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Primary Purpose: Treatment
Official Title: Phase II Study of Treatment Selection Based Upon Tumor Thymidylate Synthase Expression in Previously Untreated Patients With Metastatic Colorectal Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Response rate (complete response [CR] and partial response [PR]) as measured by RECIST [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival as measured by time to event at 1 year after closure to accrual [ Designated as safety issue: No ]
  • Overall survival as measured by time to event at 1 year after closure to accrual [ Designated as safety issue: No ]
  • Toxicity as measured by NCI CTCAE v4.0 at 1 year after closure to accrual [ Designated as safety issue: Yes ]

Estimated Enrollment: 246
Study Start Date: July 2005
Estimated Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.
Biological: bevacizumab
Given IV
Drug: fluorouracil
Given IV
Drug: irinotecan hydrochloride
Given IV
Drug: leucovorin calcium
Given IV
Experimental: Arm II
Patients receive bevacizumab and oxaliplatin as in arm I, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.
Biological: bevacizumab
Given IV
Drug: fluorouracil
Given IV
Drug: irinotecan hydrochloride
Given IV
Drug: leucovorin calcium
Given IV
Experimental: Arm III
Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm II.
Biological: bevacizumab
Given IV
Drug: fluorouracil
Given IV
Drug: irinotecan hydrochloride
Given IV
Drug: leucovorin calcium
Given IV

Detailed Description:

OBJECTIVES:

  • Compare the response rate (complete and partial), progression-free survival, and overall survival of patients with previously untreated metastatic or locally recurrent colorectal adenocarcinoma with high vs low thymidylate synthase (TS) expression treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab or irinotecan, oxaliplatin, and bevacizumab.
  • Compare the toxicity of these regimens in these patients.
  • Correlate gene expression with response rates in patients treated with these regimens.
  • Correlate gene expression with toxicity of these regimens in these patients.
  • Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian excision repair cross complementary protein expression with antitumor response in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to thymidylate synthase (TS) expression levels (high vs low or indeterminate). Patients with high TS expression are randomized to 1 of 2 treatment arms (arms I or II). Patients with low or indeterminate TS expression are assigned to arm III.

  • Arm I: Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.
  • Arm II: Patients receive bevacizumab and oxaliplatin as in arm I, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.
  • Arm III: Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm II.

In all arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Patients are followed up every 3 months for 2 years and then every 6 months for 2 years from the date of study registration.

PROJECTED ACCRUAL: A total of 117-246 patients (40-72 in arm I, 40-72 in arm II, 37-102 in arm III) will be accrued for this study within 14-23 months.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Diagnosis of colorectal adenocarcinoma

    • Metastatic or locally recurrent disease
  • Measurable disease
  • At least 2 formalin-fixed paraffin embedded core needle biopsies OR fine needle aspirate containing a minimum of 3 clusters of malignant cells and fixed tissue from the previous biopsy

    • If no tissue samples are available the patient must be willing to undergo biopsy of a metastatic site

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Performance status

  • ECOG 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3

Hepatic

  • PT (INR) ≤ 1.5 unless patient is receiving full-dose anticoagulants AND the following criteria are met:

    • In-range INR (usually between 2 and 3) AND on a stable dose of warfarin or low molecular weight heparin
    • No active bleeding or pathological condition that is associated with a high risk of bleeding
  • PTT < 1.5 times upper limit of normal (ULN)
  • ALT and AST < 3 times ULN
  • Bilirubin ≤ 1.5 times ULN
  • No hepatic disease that would preclude study therapy

Renal

  • Creatinine ≤ 1.8 mg/dL
  • Meets 1 of the following criteria:

    • Protein negative on urine dipstick
    • Urine protein/creatinine ratio < 1.0
    • Less than 2 g protein on 24-hour urine collection
  • No renal disease that would preclude study therapy

Cardiovascular

  • No arterial thromboembolic events within the past 6 months, including the following:

    • Transient ischemic attack
    • Cerebrovascular accident
    • Unstable angina pectoris
    • Myocardial infarction
  • Patients with a history of hypertension must meet the following criteria:

    • Blood pressure < 150/90 mm Hg
    • Stable regimen of anti-hypertensive therapy
  • No symptomatic arrhythmia
  • No symptomatic congestive heart failure
  • No clinically significant peripheral artery disease
  • No New York Heart Association class III or IV heart disease
  • No other cardiovascular disease that would preclude study therapy

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 3 months after study participation
  • Prior non-colorectal malignancies are allowed provided the following criteria are met:

    • No current clinical evidence of persistent or recurrent disease
    • No active therapy for non-colorectal malignancy, including hormonal therapy
  • No serious nonhealing wound, ulcer, or bone fracture within the past 28 days
  • No significant traumatic injury within the past 28 days
  • No neuropathy ≥ grade 2
  • No other nonmalignant systemic disease that would preclude study therapy
  • No ongoing or active infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

  • No prior chemotherapy for metastatic disease

    • Adjuvant therapy completed at least 12 months before first evidence of metastasis allowed

Endocrine therapy

  • Not specified

Radiotherapy

  • Not specified

Surgery

  • More than 28 days since prior major surgery
  • More than 28 days since prior open biopsy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00098787

  Show 110 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Study Chair: Neal J. Meropol, MD Fox Chase Cancer Center
Investigator: Jean L. Grem, MD University of Nebraska
  More Information

Additional Information:
No publications provided

Responsible Party: Robert L. Comis, ECOG Group Chair's Office
ClinicalTrials.gov Identifier: NCT00098787     History of Changes
Other Study ID Numbers: CDR0000398096, ECOG-E4203
Study First Received: December 8, 2004
Last Updated: July 18, 2012
Health Authority: United States: Federal Government

Keywords provided by National Cancer Institute (NCI):
recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
adenocarcinoma of the colon
adenocarcinoma of the rectum

Additional relevant MeSH terms:
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
Irinotecan
Bevacizumab
Camptothecin
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

ClinicalTrials.gov processed this record on April 14, 2014