Gemcitabine, Bevacizumab, and Abdominal Radiation Therapy in Treating Patients With Localized Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as 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 tumor growth by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Gemcitabine and bevacizumab may make tumor cells more sensitive to radiation therapy. Giving gemcitabine together with bevacizumab and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving gemcitabine together with bevacizumab and abdominal radiation therapy works in treating patients with localized pancreatic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the objective response rate in patients treated with concurrent bevacizumab, gemcitabine hydrochloride, and abdominal radiotherapy. Secondary Determine the quantitative toxicity associated with the delivery of this regimen in these patients. Determine the 1-year and median survival of patients treated with this regimen. Determine the time to progression in patients treated with this regimen. Determine the patterns of recurrence in the entire population of patients treated with this regimen and in the subgroup that is resected for cure. Determine the safety of this regimen in these patients. Evaluate the surgical experience of patients who undergo surgical resection after completion of protocol-directed therapy. Evaluate the toxicity associated with surgical resection in these patients. OUTLINE: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of courses 1 and 3 and on days 1, 8, and 15 of course 2. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15 of course 1, on days 8 and 22 of course 2, and on day 8 of course 3. Treatment repeats every 3-4 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of the second course of chemotherapy, patients undergo concurrent abdominal radiotherapy once daily, five days a week, for 3 weeks. Patients are evaluated at week 10. Patients whose disease deemed resectable after study treatment undergo standard pancreatic resection at least 6 weeks after completion of bevacizumab. Patients who remain unresectable and have not progressed after completion of chemoradiotherapy may begin maintenance therapy comprising gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment with gemcitabine hydrochloride and bevacizumab repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically for up to 10 years. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Official Title
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A Phase II Trial of Weekly Gemcitabine Hydrochloride and Bevacizumab in Combination With Abdominal Radiation Therapy in Patients With Localized Pancreatic Cancer

Conditions
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Pancreatic Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of localized pancreatic cancer No metastatic disease Resectable or unresectable tumor based on spiral CT with both oral and intravenous contrast enhancement, defined by the following National Comprehensive Cancer Network (NCCN) criteria for resectability*: Resectable tumors meeting the following criteria: No distant metastases Clear fat plane around celiac and superior mesenteric arteries Patent superior mesenteric vein/portal vein Tumors considered borderline resectable according to NCCN criteria, including any of the following, are considered unresectable for the purpose of this study: Severe unilateral superior mesenteric vein/portal impingement Tumor abutment on the superior mesenteric artery Gastroduodenal artery encasement up to the origin at the hepatic artery Colon invasion NOTE: *Determination of resectability must be made prior to study entry based on NCCN criteria Patients with biliary or gastroduodenal obstruction must have drainage or surgical bypass prior to starting chemoradiotherapy Radiographically assessable disease Malignant disease must be encompassable within a single irradiation field No gross duodenal invasion noted on endoscopy No CNS or brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-1 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for up to 3 months after completion of study therapy Bilirubin ≤ 2.0 mg/dL AST or ALT ≤ 2.5 times upper limit of normal Urine protein:creatinine ratio < 1.0 Proteinuria < 2+ by dipstick urinalysis OR baseline protein ≤ 1 g/24-hour urine collection Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9.0 g/dL (transfusion or epoetin alfa support allowed) INR ≤ 1.5 No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix, uterus, or bladder No concurrent significant infection or other medical condition that would preclude protocol treatment No history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that would contraindicate use of an investigational drug, affect the interpretation of the results of the study, or render the patient at high risk for treatment complications No clinically significant cardiac disease, including any of the following: Uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg despite antihypertensive medication) Myocardial infarction within the past year Unstable angina New York Heart Association class II-IV congestive heart failure Unstable symptomatic arrhythmia requiring medication Chronic atrial arrhythmia (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed No clinically significant peripheral vascular disease No evidence of bleeding diathesis or coagulopathy No significant traumatic injury within the past 28 days No serious, nonhealing wound or ulcer, or concurrent healing fracture No history of aneurysm, stroke, transient ischemic attack, or arteriovenous malformation No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior treatment for pancreatic cancer More than 5 years since prior chemotherapy for malignancies other than pancreatic cancer No prior radiotherapy to the target volume More than 28 days since prior major surgical procedure or open biopsy At least 28 days since prior surgical bypass More than 7 days since prior fine-needle aspiration or core biopsy No prior organ transplant At least 4 weeks since prior sorivudine or brivudine At least 30 days since prior cimetidine No concurrent major surgical procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 Arm<br>Concurrent gemcitabine, bevacizumab, and radiation therapy | Biological: bevacizumab<br>* 10 mg/kg every 2 weeks as an intravenous infusion after gemcitabine and before radiation<br>* Other names: Avastin;Drug: gemcitabine<br>* 1000 mg/m2, 30 minute intravenous infusion, cycle 1 (weeks 1, 2), cycle 2 (weeks 4, 5, 6) and cycle 3 (weeks 8 and 9). During cycle 2, gemcitabine will be delivered prior to radiation therapy<br>* Other names: gemcitabine hydrochloride;Procedure: conventional surgery<br>* If resectable, patients will undergo surgery no less than 6 weeks following last dose of bevacizumab. Unresectable patients will not undergo surgery.<br>Radiation: radiation therapy<br>* 2.4 Gy fractions, 5 fractions/week during cycle 2 only (weeks 4, 5, 6). Total dose 36 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Response will be measured by CT scans using Recist and defined as Complete Response, Partial Response, Stable disease/no response, Progressive Disease. | After 10 weeks of concurrent therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity profile of bevacizumab and gemcitabine with radiation therapy | Toxicities will be measured using National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). Adverse events (AE)are graded: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | After every cycle of therapy (cycle = 3-4 weeks), then every 3 months for 2 years, then every 6 months for 3 years, then yearly up to 10 years or until disease progression. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I pancreatic cancer, stage II pancreatic cancer, stage III pancreatic cancer