Capecitabine, Bevacizumab, and Radiation Therapy Followed By Gemcitabine and Bevacizumab in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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Drugs used in chemotherapy, such as capecitabine and gemcitabine, 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 pancreatic cancer by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Capecitabine may make tumor cells more sensitive to radiation therapy. Bevacizumab may make tumor cells more sensitive to both chemotherapy and radiation therapy. Giving chemotherapy and bevacizumab before and after radiation therapy may kill more tumor cells. This phase II trial is studying how well giving capecitabine and bevacizumab together with radiation therapy followed by gemcitabine and bevacizumab works in treating patients with locally advanced pancreatic cancer that cannot be removed by surgery.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare 1-year overall survival of patients with unresectable locally advanced pancreatic cancer treated with capecitabine, bevacizumab, and radiotherapy followed by maintenance therapy comprising gemcitabine and bevacizumab to a historical control. SECONDARY OBJECTIVES: I. Determine the frequency of serious unacceptable adverse events in patients treated with this regimen. II. Determine the response rate in patients treated with this regimen. III. Determine the progression-free survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Chemoradiotherapy and bevacizumab: Patients receive oral capecitabine twice daily and undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-38. Patients also receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Patients undergo reevaluation 3-4 weeks after completion of chemoradiotherapy and bevacizumab. Patients with no evidence of disease progression proceed to maintenance therapy. Patients with a marked response may undergo surgery at the discretion of the attending surgeon and then proceed to maintenance therapy approximately 4-8 weeks later. Maintenance therapy: Beginning within 4-7 weeks after completion of chemoradiotherapy and bevacizumab, patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30 minutes on days 1 and 15 provided that blood counts have returned to normal. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for survival. PROJECTED ACCRUAL: A total of 82 patients will be accrued for this study within 16 months.

Official Title
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A Phase II Study of Bevacizumab With Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab For Locally Advanced Pancreatic Cancer

Conditions
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Adenocarcinoma of the Pancreas, Stage II Pancreatic Cancer, Stage III Pancreatic Cancer

Intervention / Treatment
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* Drug: capecitabine
* Radiation: radiation therapy
* Biological: bevacizumab
* Procedure: therapeutic conventional surgery
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the pancreas Locally advanced disease Unresectable disease All malignant disease must be encompassable within a single irradiation field Radiographically assessable disease Patients with biliary or gastroduodenal obstruction are eligible provided drainage or surgical bypass was performed prior to initiation of study treatment No evidence of gastric outlet obstruction No evidence of duodenal invasion on CT scan No evidence of metastatic disease in the major viscera No peritoneal seeding or ascites Performance status - Zubrod 0-1 Granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 No evidence of bleeding diathesis ALT < 3 times upper limit of normal Bilirubin < 2.0 mg/dL INR ≤ 1.5 No evidence of coagulopathy Creatinine clearance > 50 mL/min Urine protein < 1,000 mg by 24-hour urine collection (for patients with proteinuria ≥ 1+ by dipstick or urinalysis OR urine protein:creatinine ratio ≥ 1.0) No myocardial infarction within the past 6 months No unstable angina within the past 6 months No arterial thromboembolic events within the past 6 months, including any of the following: Transient ischemic attack Cerebrovascular accident Clinically significant peripheral artery disease No unstable symptomatic arrhythmia requiring medication (e.g., chronic atrial arrhythmia [i.e., atrial fibrillation or paroxysmal supraventricular tachycardia]) Patients with an atrial arrhythmia are eligible provided the condition is well controlled on stable medication No New York Heart Association class II-IV congestive heart failure No history of arteriovenous malformation No history of aneurysm No uncontrolled hypertension (i.e., blood pressure > 160/90 mm Hg with medication) No other clinically significant cardiac disease No AIDS No significant infection No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies Not pregnant No nursing during and for ≥ 3-4 months after completion of study treatment Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 3-4 months after completion of study treatment No history of gastrointestinal fistula or perforation No other malignancy within the past two years except nonmelanoma skin cancer or carcinoma in situ of the cervix, uterus, or bladder No significant traumatic injury within the past 4 weeks No serious nonhealing wound or ulcer No current healing fracture No known or suspected dihydropyrimidine dehydrogenase deficiency No other medical condition that would preclude study participation No concurrent interleukin-11 No prior chemotherapy for pancreatic cancer More than 2 years since prior chemotherapy for another malignancy No prior radiotherapy to the planned irradiation field No concurrent intensity modulated radiotherapy No other concurrent radiotherapy See Disease Characteristics More than 4 weeks since prior major surgical procedure or open biopsy More than 1 week since prior fine needle aspiration or core biopsy No prior organ transplantation No concurrent major surgical procedure More than 30 days since prior and no concurrent cimetidine Concurrent ranitidine or a drug from another anti-ulcer class allowed More than 4 weeks since prior and no concurrent sorivudine or brivudine No concurrent warfarin during chemoradiotherapy Concurrent warfarin allowed beginning 2 weeks after completion of chemoradiotherapy Concurrent low molecular weight heparin allowed (at any time during study participation) No other concurrent investigational agents No other concurrent cytotoxic agents

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: Treatment (capecitabine, radiation, bevacizumab, gemcitabine)<br>Chemoradiotherapy and bevacizumab: Patients receive oral capecitabine twice daily and undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-38. Patients also receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Patients undergo reevaluation 3-4 weeks after completion of chemoradiotherapy and bevacizumab. Patients with no evidence of disease progression proceed to maintenance therapy. Patients with a marked response may undergo surgery at the discretion of the attending surgeon and then proceed to maintenance therapy approximately 4-8 weeks later. Maintenance therapy: Beginning within 4-7 weeks after completion of chemoradiotherapy and bevacizumab, patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30 minutes on days 1 and 15 provided that blood counts have returned to normal. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: capecitabine<br>* Given orally<br>* Other names: Xeloda;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | Will be estimated using the Kaplan-Meier method. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of patients developing grade 3 or greater adverse events as defined per CTCAE version 3.0 |  | Up to 1 year | 
| Progression-free survival | Will be estimated using the Kaplan-Meier method. | Up to 1 year | 
| Response rate |  | Up to 1 year |