Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance 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 hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet known whether giving more than one drug (combination chemotherapy) is more effective when given with or without bevacizumab in treating patients with metastatic colorectal cancer. PURPOSE: This randomized phase III trial is studying giving combination chemotherapy with or without bevacizumab to see how well it works in treating patients with metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Compare disease-control duration in patients with metastatic colorectal cancer receiving FOLFIRI chemotherapy in combination with bevacizumab with or without bevacizumab maintenance therapy. Secondary Determine objective response rate. Determine non-hematologic grade 3-4 (except alopecia) toxicity rate. Determine overall toxicity rate. Determine duration of chemotherapy-free interval. Determine progression-free survival. Determine overall survival. Determine time-to-treatment failure. Determine quality of life (EORTC QLQ-C30). Complete geriatric evaluation. OUTLINE: This is a multicenter study. Patients are stratified according to cancer center, primary tumor (resected vs unresected), and Köhne criteria (low vs intermediate vs high). Patients are randomized to 1 of 2 treatment arms. Arm A: Patients receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Chemotherapy treatment repeats every 2 weeks for 12 courses. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks during chemotherapy. Patients then receive bevacizumab maintenance therapy once every 2 weeks during the chemotherapy-free interval. Arm B: Patients receive FOLFIRI chemotherapy and bevacizumab as in arm A. Patients receive no treatment during the chemotherapy-free interval. In all arms, the chemotherapy treatment and the chemotherapy-free interval treatment repeats in the absence of disease progression during the chemotherapy portion or unacceptable toxicity. Patients who progress during the chemotherapy-free interval will receive 12 more courses of chemotherapy. All patients complete quality of life questionnaires (QLQ-30) and patients ≥ 75 also complete the geriatric questionnaire at baseline and every 8 weeks during study treatment. After completion of study treatment, patients are followed up every 8 weeks.

Official Title
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Multicenter Phase III Randomized Study of FOLFIRI Plus Bevacizumab Following or Not by a Maintenance Therapy With Bevacizumab in Patients With Non-Pretreated Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed colorectal cancer Metastatic disease Not a candidate for curative surgery At least 1 tumor target measurable by RECIST criteria No metastasis potentially resectable after receiving chemotherapy No occlusive tumors No macronodular peritoneal carcinomatosis No known or suspected CNS metastases PATIENT CHARACTERISTICS: OMS status 0-2 Life expectancy ≥ 3 months ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of hepatic metastases) Creatinine ≤ 1.5 times ULN Proteinuria ≤1 g Not pregnant or nursing No gastroduodenal ulcer, wound, or fractured bone No acute or subacute intestinal occlusion or history of inflammatory bowel disease or large resection of small bowel No clinically relevant coronary artery disease or a history of a myocardial infarction within the last 6 months No uncontrolled hypertension while receiving chronic medication No other malignancy within the past 5 years except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix No medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study PRIOR CONCURRENT THERAPY: See Patient Characteristics No prior chemotherapy for metastatic disease Adjuvant chemotherapy allowed provided it was completed > 6 months ago No prior irinotecan or other antiangiogenic therapy At least 4 weeks since surgery (except for diagnostic biopsy) or irradiation No other drugs not allowed for medical reasons Concurrent oral anticoagulants (e.g., coumadin, warfarin) allowed provided the INR is closely monitored A change of anticoagulants to low-molecular weight heparin is preferred

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Maintenance with bevacizumab<br>FOLFIRI + Avastin and during the chemotherapy-free interval maintenance with bevacizumab | Biological: bevacizumab<br> <br> Drug: FOLFIRI regimen<br> <br> Drug: fluorouracil<br> <br> Drug: irinotecan hydrochloride<br> <br> Drug: leucovorin calcium<br> <br> |
| Active Comparator: No maintenance with bevacizumab<br>FOLFIRI + Avastin and during the chemotherapy-free interval NO maintenance | Biological: bevacizumab<br> <br> Drug: FOLFIRI regimen<br> <br> Drug: fluorouracil<br> <br> Drug: irinotecan hydrochloride<br> <br> Drug: leucovorin calcium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-control duration |  | one year after last patient included | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | one year after last patient is included | 
| Rate of non-hematologic grade 3-4 toxicities (except alopecia) |  | one year after last patient is included | 
| Overall toxicity rate |  | one year after last patient is included | 
| Duration of chemotherapy-free interval |  | one year after last patient is included | 
| Progression-free survival |  | one year after last patient is included | 
| Overall survival |  | one and 2 year after last patient is included | 
| Time-to-treatment failure |  | one year after last patient is included | 
| Quality of life as assessed by EORTC QLQ-C30 |  | one year after last patient is included | 
| Geriatric evaluation |  | one year after last patient is included | 

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