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

Study Overview
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Brief Summary
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Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without bevacizumab in treating patients who have advanced or metastatic colorectal cancer that has been previously treated. Drugs used in chemotherapy use 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. Combining monoclonal antibody therapy with combination chemotherapy may kill more tumor cells. It is not yet known if bevacizumab is more effective with or without combination chemotherapy in treating colorectal cancer

Detailed Description
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OBJECTIVES: I. 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). II. Compare the toxicity of these regimens in these patients. 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.

Official Title
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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

Conditions
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Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage III Colon Cancer, Stage III Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: oxaliplatin
* Drug: leucovorin calcium
* Drug: fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Performance status - ECOG 0-2 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No history of thrombotic or hemorrhagic disorders 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 Creatinine no greater than 1.5 times ULN Proteinuria less than 1+ (i.e., 0 or trace) Protein less than 500 mg by 24-hour urine collection Proteinuria secondary to ureteral stents allowed No proteinuria secondary to nephropathy 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 No serious nonhealing wound, ulcer, or bone fracture Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior bevacizumab See Disease Characteristics Recovered from prior chemotherapy No prior oxaliplatin At least 2 weeks since prior radiotherapy and recovered At least 28 days since prior major surgical procedure 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (bevacizumab, oxaliplatin, leucovorin, fluorouracil)<br>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. | Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;|
| Experimental: Arm II (oxaliplatin, leucovorin calcium, fluorouracil)<br>Patients receive oxaliplatin, leucovorin calcium, and 5-FU as in arm I. | Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;|
| Experimental: Arm III (bevacizumab)<br>Patients receive bevacizumab as in arm I. | Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | From the date of entry on study, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response defined using RECIST criteria |  | Up to 5 years | 
| Progression free survival |  | From the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression, assessed up to 5 years |