Capecitabine, Oxaliplatin, and Bevacizumab in Treating Patients With Metastatic or Recurrent Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine, and oxaliplatin, 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 find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine and oxaliplatin together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving oxaliplatin and capecitabine together with bevacizumab works in treating patients with metastatic or recurrent colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Evaluate the response rate in patients with previously untreated metastatic colorectal cancer treated with capecitabine, oxaliplatin, and bevacizumab. Secondary Assess time to progression (TTP), disease-free survival (DFS), and overall survival (OS) in patients treated with this regimen. Assess the safety and tolerability of bevacizumab, oxaliplatin, and capecitabine in patients with previously untreated metastatic colorectal cancer. Exploratory Evaluate the effect of this regimen on the biomarkers of angiogenesis. Assess the effect of this regimen on wound angiogenesis. OUTLINE: Patients receive oral capecitabine twice daily on days 1-5 and 8-12, oxaliplatin IV over 2 hours on day 1, and bevacizumab IV over 1-1½ hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
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Phase II Study of Oxaliplatin, Capecitabine and Bevacizumab in the Treatment of Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: oxaliplatin
* Drug: Capecitabine
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically documented adenocarcinoma of the colon or rectum Metastatic or recurrent disease not amenable to potentially curative treatment (e.g., inoperable metastatic disease) No leptomeningeal or brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute neutrophil count ≥ 2,000/mm^3 Platelet count ≥ 100,000/mm^3 AST/ALT < 2.5 times upper limit of normal (ULN) (5 times ULN if known liver metastases) Bilirubin < 1.5 times ULN Creatinine clearance > 50 mL/min No unstable or poorly controlled hypertension (> 150/100 mm Hg) Patients who have recently started or adjusted antihypertensive medications are eligible provided blood pressure is < 140/90 mm Hg on any new regimen for at least 3 different observations over 14 days Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during study and for at least 3-4 months after study completion No arterial or venous thrombosis (including cerebrovascular accident) within the last 3 months No known, existing, uncontrolled coagulopathy No clinically significant cardiac disease No congestive heart failure No symptomatic coronary artery disease No cardiac arrhythmias not well controlled with medication No myocardial infarction within the last 12 months No history of allergic reactions attributed to compounds of similar chemical or biologic composition to oxaliplatin, capecitabine, or bevacizumab No history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the patient at high risk from treatment complications PRIOR CONCURRENT THERAPY: At least 4 weeks since prior sorivudine or brivudine At least 6 months since prior adjuvant treatment with fluorouracil and leucovorin calcium or a fluorouracil and leucovorin calcium-based regimen No major surgery within 4 weeks without complete recovery No prior chemotherapy for metastatic/recurrent disease No cancer immunotherapy or other biologic therapy while on therapy No radiotherapy while on study No hormonal therapy for cancer while on study No full-dose warfarin (INR of > 1.5), heparin (> 10,000 units/day), or thrombolytic agents Allopurinol and cimetidine should be discontinued prior to starting on this regimen

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Initial Cohort<br> | Biological: bevacizumab<br>* 10 mg/kg intravenously over 30-90 minutes on day 1<br>Drug: oxaliplatin<br>* 85 mg/m2 intravenously over 2 hours on day 1.<br>Drug: Capecitabine<br>* Oral administration every 12 hours on days 1-5 and 8-12 1000 mg/m2 in initial cohort<br>|
| Experimental: Second cohort<br> | Biological: bevacizumab<br>* 10 mg/kg intravenously over 30-90 minutes on day 1<br>Drug: oxaliplatin<br>* 85 mg/m2 intravenously over 2 hours on day 1.<br>Drug: Capecitabine<br>* Oral administration every 12 hours on days 1-5 and 8-12 850 mg/m2 in second cohort<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Percentage of Participants With Partial or Complete Response) | Restaging scans occurred every 9 weeks from time of study drug initiation until disease progression. Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. The definitions were: Complete response (CR)- Disappearance of all target lesions Partial response (PD)- At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Stable disease (SD)- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive disease (PD) - At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions | After all subjects were evaluated for restaging which occured every 9 weeks from drug initiation until disease progression, assesed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | From time of treatment until documented progression, assesed up to 60 months. | 
| Disease Free Survival | Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | From time of treatment until documented progression or death from any cause, whichever came first, assesed up to 60 months. | 
| Overall Survival | Average months of survival of participants after receiving study drug. | From time of treatment until death from any cause, assesed up to 60 months. | 
| Safety and Tolerability | Number of participants with adverse events | After all participants went off study drug regimine. | 

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