S0408: Capecitabine, Oxaliplatin, and Bevacizumab in Pts Undergoing Surgery for Liver Mets From 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 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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine and oxaliplatin together with bevacizumab before and after surgery may be an effective treatment for liver metastases. PURPOSE: This phase II trial is studying how well giving capecitabine and oxaliplatin together with bevacizumab works in treating patients who are undergoing surgery for liver metastases due to colorectal cancer.

Detailed Description
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OBJECTIVES: Determine the proportion of patients with resectable hepatic metastases secondary to colorectal cancer who undergo surgical resection and achieve a R0 resection after treatment with neoadjuvant capecitabine, oxaliplatin, and bevacizumab. Determine the probability of non-progression (i.e., stable disease or response [complete and partial, confirmed and unconfirmed]) in patients treated with this regimen. Compare the proportion of patients treated with this regimen who undergo surgical resection and those who achieve a R0 resection with that described in the literature. Determine overall survival and disease-free survival of patients treated with this regimen. Determine response by positron emission tomography in patients treated with this regimen. Correlate clinical outcome with expression of biomarkers (e.g., thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, excision repair cross complementing 1, and hTERT) and telomere length in patients treated with this regimen. OUTLINE: This is a multicenter study. Neoadjuvant therapy: Patients receive bevacizumab* IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. NOTE: *Bevacizumab is administered during courses 1-3 of neoadjuvant therapy. Surgery: Approximately 3-4 weeks after completion of neoadjuvant therapy, patients are evaluated. Patients with unresectable disease are removed from the study. Patients with resectable disease undergo surgical resection of liver metastases within 4-6 weeks after completion of neoadjuvant therapy. Adjuvant therapy: Beginning at least 28 days after surgical resection, patients with at least stable disease after completion of neoadjuvant therapy receive 4 courses of adjuvant bevacizumab**, oxaliplatin, and capecitabine as in neoadjuvant therapy. NOTE: **Bevacizumab is administered during courses 1-4 of adjuvant therapy. After completion of study treatment, patients are followed every 4 months until disease progression and then every 6 months for up to 3 years from study entry. PROJECTED ACCRUAL: Approximately 35-65 patients will be accrued for this study.

Official Title
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A Phase II Trial of Neoadjuvant Capecitabine, Oxaliplatin, and Bevacizumab for Resectable Colorectal Metastases in the Liver

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: capecitabine
* Drug: oxaliplatin
* Procedure: conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of hepatic metastases secondary to colorectal cancer by percutaneous hepatic biopsy Resectable hepatic metastases by any of the following: Minor resection (i.e., less than a hemihepatectomy) Major resection (i.e., hemihepatectomy or extended hepatectomy) Bilobar resection (including atypical resection) Synchronous primary tumor and hepatic metastases allowed Radiologic evidence of hepatic metastases by multiphasic contrast-enhanced spiral CT scan Resectable primary colorectal cancer that is in place allowed Measurable disease No evidence of extrahepatic metastases by chest x-ray or CT scan of the chest PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic Hemoglobin ≥ 9.0 g/dL WBC ≥ 3,000/mm^3 Platelet count ≥ 100,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) SGOT or SGPT ≤ 2.5 times ULN Renal Creatinine clearance ≥ 60 mL/min Urine protein/creatinine ratio < 1 OR Urine protein < 1 g by 24-hour urine collection Cardiovascular No uncontrolled hypertension (i.e., blood pressure > 150/90 mm Hg) History of hypertension allowed provided it is well controlled on a stable regimen of anti-hypertensive therapy No arterial thromboembolic event within the past 12 months, including any of the following: Transient ischemic attack Cerebrovascular accident Unstable angina Myocardial infarction No peripheral vascular disease ≥ grade 2 Other Not pregnant or nursing Fertile patients must use effective contraception No pre-existing peripheral neuropathy ≥ grade 2 No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy More than 6 months since prior adjuvant chemotherapy for the primary tumor No prior systemic chemotherapy for metastatic disease No prior hepatic artery infusion chemotherapy for metastatic disease Endocrine therapy Not specified Radiotherapy No prior radiotherapy for metastatic disease Surgery More than 7 days since prior colonoscopy or fine needle aspiration More than 28 days since prior major invasive surgery or open biopsy Other At least 4 weeks since prior and no concurrent sorivudine or brivudine No prior radiofrequency ablation for metastatic disease No prior cryotherapy for metastatic disease No other prior ablative techniques for metastatic disease No concurrent cimetidine Concurrent ranitidine or other drug from a different antiulcer class allowed No concurrent oral anticoagulation for treatment of thrombosis Concurrent warfarin (1 mg) to maintain patency of central venous catheter allowed

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy + Surgery + Chemotherapy<br>Preoperative Neoadjuvant Chemotherapy Bevacizumab, 7.5 mg/kg, IV, Day 1 of cycles 1,2,3 Oxaliplatin, 130 mg/m^2, IV, Day 1 of cycles 1,2,3,4 Capecitabine, 1,700 mg/m^2/day divided, PO at 12 hr intervals, Days 1-14 of cycles 1,2,3,4 Conventional surgery: After 4 cycles of chemotherapy Postoperative Neoadjuvant Chemotherapy Bevacizumab, 7.5 mg/kg, IV, Day 1 of cycles 1,2,3,4 Oxaliplatin, 130 mg/m^2, IV, Day 1 of cycles 1,2,3,4 Capecitabine, 1,700 mg/m^2/day divided, PO at 12 hr intervals, Days 1-14 of cycles 1,2,3,4 | Biological: bevacizumab<br>* Preoperative: 7.5 mg/kg, IV, Day 1 of cycles 1,2,3 Postoperative: 7.5 mg/kg, IV, Day 1 of cycles 1,2,3,4<br>* Other names: NSC-704865;Drug: capecitabine<br>* Pre & Post Operative: 1,700 mg/m^2/day, PO at 12 hr interval, Days 1-14 of cycles 1,2,3,4<br>* Other names: NSC-712807;Drug: oxaliplatin<br>* 130 mg/m^2, IV, Day 1 of cycles 1,2,3,4<br>* Other names: NSC-266046;Procedure: conventional surgery<br>* Resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with R0 resection after treatment |  | 16-18 weeks from registration | 
| Probability of nonprogression (i.e., stable disease or response [complete and partial, confirmed and unconfirmed]) |  | 12 weeks from registration | 
| Comparison of patients achieving R0 resection with literature |  | 16-18 weeks from registration | 
| Overall survival |  | Up to 3 years | 
| Disease-free survival |  | Up to 3 years | 
| Positron emission tomography response |  | Registration and 12 weeks | 
| Correlation of clinical outcome with expression of biomarkers and telomere length |  | Up to 3 years | 

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