Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as irinotecan, 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. Giving combination chemotherapy together with bevacizumab may kill more tumor cells. PURPOSE: This randomized phase III trial is comparing two combination chemotherapy regimens given together with bevacizumab to see how well they work as first-line therapy in treating patients with metastatic colorectal cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To compare the progression-free survival of bevacizumab in combination with oxaliplatin, irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFOXIRI) versus bevacizumab in combination with irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with unresectable, metastatic colorectal cancer. Secondary To evaluate the safety profile, including long-term adverse events of these regimens in these patients. To compare the overall response rate, duration of response, and secondary R0 surgery rates of metastases and overall survival between treatment arms. To evaluate potential surrogate markers predictive of bevacizumab activity. OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1-2), prior adjuvant chemotherapy (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms. Arm I (FOLFOXIRI): Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1. Arm II (FOLFIRI): Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1. In both arms, treatment repeats every 2 weeks for up to 12 courses. Treatment with bevacizumab, fluorouracil, and leucovorin calcium continues in the absence of disease progression or unacceptable toxicity. Patients undergo serum extraction and blood sample collection periodically for genotyping studies. Patients also undergo collection of tumoral sections from paraffin embedded primary and/or metastatic lesions periodically for immunohistochemical analyses. After completion of study treatment, patients are followed every 8 weeks.

Official Title
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A PHASE III RANDOMIZED TRIAL OF FOLFOXIRI + BEVACIZUMAB VERSUS FOLFIRI + BEVACIZUMAB AS FIRST- LINE TREATMENT FOR METASTATIC COLORECTAL CANCER

Conditions
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Colorectal Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed colorectal cancer Unresectable metastatic disease Measurable disease, defined as ≥ 1 measurable lesion according to RECIST criteria No prior chemotherapy for metastatic disease No untreated brain metastases, spinal cord compression, or primary brain tumors No history or evidence of CNS disease by physical examination unless adequately treated (e.g., uncontrolled seizure despite standard medical therapy or history of stroke) PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status (PS) 0-2 (≤ 70 years of age) OR ECOG PS 0 (71-75 years of age) Life expectancy ≥ 12 weeks Neutrophils ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Hemoglobin > 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN if f liver metastases present) Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases present) Creatinine clearance > 50 mL/min OR serum creatinine ≤ 1.5 times ULN Proteinuria < 2+ by dipstick OR urine protein ≤ 1 g by 24-hr urine collection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Exclusion criteria: Serious, nonhealing wound, ulcer, or bone fracture Evidence of bleeding diathesis or coagulopathy Uncontrolled hypertension Clinically significant (i.e., active) cardiovascular disease, including any of the following: Cerebrovascular accidents within the past 6 months Myocardial infarction within the past 6 months Unstable angina New York Heart Association class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Known allergy to Chinese hamster ovary cell proteins or any of the components of the study medications Other co-existing malignancy or malignancy diagnosed within the past 5 years, except for basal cell or squamous cell carcinoma, or carcinoma in situ of the cervix Symptomatic peripheral neuropathy ≥ grade 1 according to the NCI Common Toxicity Criteria Lack of physical integrity of the upper gastrointestinal tract Malabsorption syndrome Inability to take oral medication Significant traumatic injury within the past 28 days PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior radiotherapy More than 10 days since prior and no concurrent ongoing treatment with anticoagulants for therapeutic purposes More than 28 days since prior and no concurrent major surgical procedure More than 28 days since prior open biopsy More than 30 days since prior investigational agents No concurrent chronic daily high-dose acetylsalicylic acid (> 325 mg/day)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 (FOLFOXIRI)<br>Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1. | Biological: bevacizumab<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>Drug: leucovorin calcium<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>|
| Experimental: Arm II (FOLFIRI)<br>Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1. | Biological: bevacizumab<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>Drug: leucovorin calcium<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | To compare the progression free survival of bevacizumab in combination with oxaliplatin, irinotecan and infusional 5FU/LV (GONO FOLFOXIRI regimen) to bevacizumab in combination with irinotecan and infusional 5FU/LV (FOLFIRI regimen) | up to 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate |  | up to 54 months | 
| Duration of response |  | up to 54 months | 
| Secondary R0 surgery rates of metastases |  | up to 54 months | 
| Overall survival |  | up to 54 months | 
| Surrogate markers predictive of bevacizumab activity |  | up to 54 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV rectal cancer, stage IV colon cancer, stage III rectal cancer, stage III colon cancer