Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Bevacizumab Compared With Bevacizumab Alone in Treating Patients With Advanced or Metastatic Colorectal Cancer That Has Been Previously Treated

Basic Trial Information

Special Category: CTSU trial

Objectives

1. Compare the response, time to progression, and overall survival of patients with previously treated advanced or metastatic colorectal adenocarcinoma treated with oxaliplatin, leucovorin calcium, and fluorouracil with or without bevacizumab versus bevacizumab only. (Arm III closed to accrual as of 03/11/2003).
2. Compare the toxicity of these regimens in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed adenocarcinoma of the colon or rectum
  • Advanced or metastatic disease
  • Must have received a fluoropyrimidine-based regimen and an irinotecan-based regimen, either alone or in combination, for advanced disease
  • May have relapsed within 6 months of adjuvant therapy with fluorouracil (5-FU) (or combination 5-FU and irinotecan) and progressed after single-agent irinotecan
• Measurable disease
• No known brain metastases

Prior/Concurrent Therapy:

Biologic therapy:

• No prior bevacizumab

Chemotherapy:

• See Disease Characteristics
• Recovered from prior chemotherapy
• No prior oxaliplatin

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 2 weeks since prior radiotherapy and recovered

Surgery:

• At least 28 days since prior major surgical procedure

Other:

• At least 10 days since prior aspirin dose of more than 325 mg/day
• No concurrent therapeutic anticoagulation except prophylactic anticoagulation of venous access device
• No concurrent antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, or cilostazol)
• No concurrent oral cryotherapy on day 1 of oxaliplatin administration

Patient Characteristics:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• No history of thrombotic or hemorrhagic disorders

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST no greater than 5 times ULN
• INR no greater than 1.5
• PTT no greater than ULN

Renal:

• Creatinine no greater than 1.5 times ULN
• Proteinuria less than 1+ (i.e., 0 or trace)

  OR

• Protein less than 500 mg by 24-hour urine collection
• Proteinuria secondary to ureteral stents allowed
  • No proteinuria secondary to nephropathy

Cardiovascular:

• Controlled hypertension (less than 150/100 mm Hg) allowed if on a stable antihypertensive regimen
• No prior myocardial infarction
• No uncontrolled congestive heart failure
• No unstable angina within the past 3 months

Other:

• No serious nonhealing wound, ulcer, or bone fracture
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 880 patients (293 per treatment arm) will be accrued for this study within 18 months. (Arm III closed to accual as of 03/11/2003).

Outline

This is a randomized study. Patients are stratified according to ECOG performance status (0 vs 1 or 2), and prior radiotherapy (yes vs no). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1 and 2.
• Arm II: Patients receive oxaliplatin, leucovorin calcium, and 5-FU as in arm I.
• Arm III: Patients receive bevacizumab as in arm I. (Arm closed to accrual as of 03/11/2003).

Courses in all arms repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response may receive 2 additional courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Catalano PJ, Mitchell EP, Giantonio BJ, et al.: Outcomes differences for African Americans and Caucasians treated with bevacizumab, FOLFOX4 or the combination in patients with metastatic colorectal cancer (MCRC): results from the Eastern Cooperative Oncology Group Study E3200. [Abstract] J Clin Oncol 25 (Suppl 18): A-4100, 2007.

Giantonio BJ, Catalano PJ, Meropol NJ, et al.: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25 (12): 1539-44, 2007.[PUBMED Abstract]

Giantonio BJ, Catalano PJ, O'Dwyer PJ, et al.: Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group's study E3200. [Abstract] J Clin Oncol 24 (Suppl 18): A-3538, 2006.

Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005.

Mitchell EP, Alberts SR, Schwartz MA, et al.: High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] American Society of Clinical Oncology 2005 Gastrointestinal Cancers Symposium, 27-29 January 2005, Miami, Florida. A-169a, 2005.

Giantonio BJ, Chen HX, Catalano PJ, et al.: Bowel perforation and fistula formation in colorectal cancer patients treated on Eastern Cooperative Oncology Group (ECOG) studies E2200 and E3200. [Abstract] J Clin Oncol 22 (Suppl 14): A-3017, 199s, 2004.

Benson AB, Catalano PJ, Meropol NJ, et al.: Bevacizumab (anti-VEGF) plus FOLFOX4 in previously treated advanced colorectal cancer (advCRC): an interim toxicity analysis of the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-975, 2003.

Cassidy J, Saltz LB, Giantonio BJ, et al.: Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol 136 (5): 737-43, 2010.[PUBMED Abstract]

Giantonio BJ, Meropol NJ, Catalano PJ, et al.: Magnitude of progression-free survival (PFS) improvement and treatment (Tx) duration in metastatic colorectal cancer (mCRC) for bevacizumab (BV) in combination with oxaliplatin-containing regimens: an analysis of two phase III studies. [Abstract] J Clin Oncol 25 (Suppl 18): A-4073, 2007.

Saif MW, Mehra R: Incidence and management of bevacizumab-related toxicities in colorectal cancer. Expert Opin Drug Saf 5 (4): 553-66, 2006.[PUBMED Abstract]

Gray R, Giantonio BJ, O'Dwyer PJ, et al.: The safety of adding angiogenesis inhibition into treatment for colorectal, breast, and lung cancer: the Eastern Cooperative Oncology Group's (ECOG) experience with bevacizumab (anti-VEGF). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-825, 2003.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Bruce Giantonio, MD, Protocol chair(Contact information may not be current)		Ph: 215-503-4500; 800-533-3669

Registry Information
Official Title		Phase III Trial of Bevacizumab (NSC 704865), Oxaliplatin (NSC 266046), Fluorouracil and Leucovorin Versus Oxaliplatin, Fluorouracil and Leucovorin Versus Bevacizumab Alone in Previously Treated Patients with Advanced Colorectal Cancer
Trial Start Date		2001-10-30
Trial Completion Date		2007-04-20
Registered in ClinicalTrials.gov		NCT00025337
Date Submitted to PDQ		2001-08-13
Information Last Verified		2003-01-06
NCI Grant/Contract Number		CA21115

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