Capecitabine, Cetuximab, Oxaliplatin, and Bevacizumab in Treating Patients With Metastatic or Recurrent Colorectal Cancer That Cannot Be Removed By Surgery

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. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as cetuximab and 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. Cetuximab and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab works in treating patients with metastatic or recurrent colorectal cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the response rate in patients with unresectable metastatic or recurrent colorectal adenocarcinoma treated with capecitabine, cetuximab, oxaliplatin, and bevacizumab. Secondary Determine the safety and tolerability of this regimen in these patients. Determine the progression-free and overall survival of patients treated with this regimen. Exploratory Determine the effect of this regimen on the angiogenesis biomarkers in these patients. Determine the effect of this regimen on wound angiogenesis in these patients. OUTLINE: This is a multicenter study. Patients receive oral capecitabine twice daily on days 1-14. Patients will also receive cetuximab IV over 1-2 hours, oxaliplatin IV over 2 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 1 month. PROJECTED ACCRUAL: Approximately 45 patients will be accrued for this study.

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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Biological: cetuximab
* Drug: capecitabine
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the colon or rectum Unresectable disease Metastatic or recurrent disease Not amenable to potentially curative treatment No untreated leptomeningeal or brain metastases PATIENT CHARACTERISTICS: Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 2,000/mm^3 Platelet count ≥ 100,000/mm^3 No known uncontrolled coagulopathy Hepatic AST and ALT < 2.5 times upper limits of normal (ULN) (5 times ULN if liver metastases are present) Bilirubin < 2.0 times ULN Renal Creatinine clearance > 40 mL/min Urine protein negative Urine protein:creatinine ratio > 1 Cardiovascular No unstable or uncontrolled hypertension (i.e., blood pressure [BP] > 150/100 mm Hg despite antihypertensive therapy) Patients who recently started or have adjusted antihypertensive medications are eligible provided BP is < 140/90 mm Hg for ≥ 3 different measurements over 14 days No arterial thromboembolic events within the past 6 months, including any of the following: Transient ischemic attack Cerebrovascular accident Unstable angina Myocardial infarction Clinically significant peripheral vascular disease No New York Heart Association class III-IV congestive heart failure No uncontrolled symptomatic coronary artery disease or cardiac arrhythmia No other significant uncontrolled cardiac disease Gastrointestinal No lack of physical integrity of the upper gastrointestinal tract No malabsorption syndrome No inability to tolerate oral medication Immunologic No prior severe infusion reaction to a monoclonal antibody No history of an allergic reaction attributed to compounds of similar chemical or biologic composition to oxaliplatin, cetuximab, capecitabine, or bevacizumab No prior unanticipated, severe reaction to fluoropyrimidine therapy or known hypersensitivity to fluoroucacil Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during the study and for 3-4 months after completion of study treatment No peripheral neuropathy ≥ grade 2 No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix No known dihydropyrimidine dehydrogenase deficiency PRIOR CONCURRENT THERAPY: Biologic therapy No prior adjuvant bevacizumab or cetuximab No other concurrent anticancer immunotherapy or biologic therapy Chemotherapy At least 6 months since a prior adjuvant fluorouracil-, leucovorin calcium-, or capecitabine-based regimen At least 12 months since prior adjuvant oxaliplatin No prior chemotherapy for metastatic or recurrent disease Endocrine therapy No concurrent hormonal therapy Radiotherapy No concurrent radiotherapy Surgery More than 4 weeks since prior major surgery and recovered More than 6 months since vascular surgery, stenting, or angioplasty Other At least 4 weeks since prior and no concurrent sorivudine or brivudine More than 4 weeks since prior participation in any investigational drug study No prior therapy that affects or targets the epidermal growth factor pathway No concurrent cimetidine Concurrent ranitidine, famotidine, or proton-pump inhibitors allowed Concurrent anticoagulation therapy with full-dose anticoagulant allowed provided dose is stable for at least 2 weeks

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: Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab<br>Capecitabine - oral administration of 850 mg/m2 every 12 hours on days 1-14. Oxaliplatin - IV administration of 130 mg/m2 over 2 hours on day 1 of a cycle. Bevacizumab- IV administration of 7.5 mg/kg over 30-90 minutes on day 1 of a cycle. Cetuximab at an initial dose of 400 mg/m2 over 120 minutes and subsequently 250 mg/m2 over 60 minutes on day 1 of a cycle. Cycles are 21 days. | Biological: bevacizumab<br> <br> * Other names: Avastin;Biological: cetuximab<br> <br> Drug: capecitabine<br> <br> Drug: oxaliplatin<br> <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 |
| --- | --- | --- |
| Safety and Tolerability | Number of participants with adverse events | After all participants went off study drug regimine. | 
| Progression-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. This is the average number of months participants survived without showing progressive disease. | 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. | 

 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