Second-Line Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer Who Have Received First-Line Chemotherapy and Bevacizumab

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. It is not yet known whether combination chemotherapy is more effective with or without bevacizumab in treating metastatic colorectal cancer. PURPOSE: This randomized phase III trial is studying second-line combination chemotherapy to see how well it works compared with or without bevacizumab in treating patients with metastatic colorectal cancer who have received first-line chemotherapy and bevacizumab.

Detailed Description
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OBJECTIVES: Primary To compare the progression-free survival of second-line chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer who have received first-line chemotherapy with bevacizumab. Secondary To compare the overall survival, response rate, and safety profile of second-line chemotherapy of these regimens in these patients. To conduct pharmacogenomics assessment of candidate variants in the VEGF gene and evaluate their association with progression-free survival and other study outcomes. OUTLINE: This is a multicenter study. Patients are stratified according to participating center, ECOG performance status (0 vs 1-2), disease-free interval from the last administration of first-line chemotherapy for metastatic disease (≤ 3 months vs > 3 months), and type of second-line chemotherapy (irinotecan hydrochloride, leucovorin calcium, and fluorouracil [FOLFIRI] vs oxaliplatin, leucovorin calcium, and fluorouracil [mFOLFOX-6]). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over 1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil IV over 46 hours continuously beginning on day 1. Arm II: Patients receive combination chemotherapy as in arm I and bevacizumab IV on day 1. Treatment in both arms repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Existing formalin-fixed paraffin-embedded tumor tissue samples are assessed for pharmacogenomics and markers predictive of response, resistance to, or toxicity from bevacizumab. Samples are analyzed via RT-PCR, array comparative genomic hybridization, fluorescence in situ hybridization, sequencing of candidate genes, and immunohistochemistry. After completion of study treatment, patients are followed for 1 year.

Official Title
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AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB.

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 adenocarcinoma Metastatic or unresectable disease Progressive disease based on the following criteria: Progression during or after first-line chemotherapy for metastatic disease, including any of the following: Fluoropyrimidine-based monotherapy with bevacizumab Fluoropyrimidine and irinotecan hydrochloride-based doublet with bevacizumab Fluoropyrimidine and oxaliplatin-based doublet with bevacizumab Progression after more than 3 months from the last administration of first-line chemotherapy for metastatic disease with a fluoropyrimidine, irinotecan hydrochloride, and oxaliplatin triplet (FOLFOXIRI) with bevacizumab to which the patient had previously responded Measurable disease, as assessed by RECIST criteria No prior or concurrent CNS metastasis PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 3 months ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL INR ≤ 1.5 times upper limit of normal (ULN) aPTT ≤ 1.5 ULN Serum bilirubin ≤ 1.5 times ULN AST and ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases present) Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if liver metastases present) Serum creatinine ≤ 1.5 times ULN Proteinuria < 2+ OR protein ≤ 1g by 24-hour urine Not pregnant or nursing Fertile patients must use effective contraception No bowel obstruction or subobstruction No history of inflammatory enteropathy No prior extensive intestinal resection (i.e., > hemicolectomy or extensive small intestine resection with chronic diarrhea) No symptomatic peripheral neuropathy > grade 2 No active uncontrolled infection No active disseminated intravascular coagulation No prior or concurrent malignancy, except for curatively treated basal cell and squamous cell carcinoma of the skin, or in situ carcinoma of the cervix No clinically significant cardiovascular disease, including any of the following: Cerebrovascular accident within the past 6 months Myocardial infarction within the past 6 months Unstable angina NYHA class II-IV chronic heart failure Uncontrolled arrhythmia No uncontrolled hypertension No thromboembolic or hemorrhagic events within the past 6 months No evidence of bleeding diathesis or coagulopathy No serious, non healing wound/ulcer or serious bone fracture No significant traumatic injury within the past 28 days PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 6 weeks since prior radiotherapy At least 4 weeks since prior surgery No prior first-line chemotherapy for metastatic disease without bevacizumab No prior cetuximab or other investigational agents More than 28 days since prior open biopsy More than 28 days since prior and no concurrent major surgical procedure No concurrent therapeutic anticoagulation, antiplatelet agents, or NSAID with anti-platelet activity Acetylsalicylic acid ≤ 325 mg/day allowed

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 |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over 1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil IV over 46 hours continuously beginning on day 1. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. | 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<br>Patients receive combination chemotherapy as in arm I and bevacizumab IV on day 1. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. | 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | last progression of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | the end of the stady | 
| Response rate |  | last visit of the last patient | 
| Safety |  | the end of the study | 

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