Bevacizumab, Erlotinib and Capecitabine for Advanced Pancreatic Cancer

Inclusion Criteria:

1. ECOG performance status of 0 or 1.
2. Patients must be \>/= 18 years of age. There will be no upper age restriction.
3. Cytologic or histologic proof of adenocarcinoma of the pancreas. Patients can have tumor originating in any part of the pancreas. Islet cell tumors are not eligible. Only patients with non- metastatic, unresectable disease are eligible. Patients who cannot undergo resection because of underlying medical problems are also eligible. Patients with regional nodal disease are eligible.
4. All patients must be staged with a physical exam, CXR, and contrast-enhanced helical thin-cut abdominal CT. Unresectability is defined by CT criteria: a) evidence of tumor extension to the celiac axis or superior mesenteric (SM) artery, or b) evidence on either CT or angiogram of occlusion of the SM vein or SM/ portal vein confluence. If a tumor does not meet this definition and is found to be unresectable at surgical exploration, then that tumor is considered unresectable.
5. Patients may have received prior chemotherapy but not prior radiation therapy to the upper abdomen.
6. Bone marrow function: absolute neutrophil count (ANC) \>1,500/ul. Platelets \>100,000/ul.
7. Hepatic function: Total bilirubin less than 5mg/dL. If the patient required an endobiliary stent, the bilirubin level must have declined on consecutive measurements indicating adequate biliary decompression; alanine aminotransferase (ALT) \</= 5 times the upper limit of normal.
8. Renal function: BUN \</= 30 mg%, creatinine \</= 1.5 mg% and creatinine clearance \>/= 30ml/min (estimated as calculated with Cockcroft-Gault equation). Note: In patients with moderate renal impairment (estimated creatinine clearance 30-50 mL/min) at baseline, a dose reduction to 75% of the capecitabine starting dose is recommended.
9. Patients must have signed informed consent indicating that they are aware of the investigational nature of the study, and are aware that participation is voluntary.

Exclusion Criteria:

1. Prior abdominal radiotherapy.
2. Imaging (CT or MRI) or endoscopic evidence of direct duodenal invasion by tumor.
3. Prior therapy with bevacizumab, cetuximab, or gefitinib. Prior therapy with erlotinib is permitted unless the patient was taken off erlotinib due to treatment failure.
4. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study.
5. Prior severe infusion reaction (bronchospasm, stridor, urticaria and/or hypotension) to a monoclonal antibody.
6. Prior unanticipated severe reaction to fluoropyrimidine therapy or known hypersensitivity to 5-fluorouracil.
7. Proteinuria at baseline or clinically significant impairment of renal function as demonstrated by urine dipstick for proteinuria \>/= 2+ (patients discovered to have \>/= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate \</= 1g of protein in 24 hours to be eligible).
8. Prior history of cancer within the last five years except for basal cell carcinoma of the skin or carcinoma in situ of the cervix. Patients with previous malignancies but without evidence of disease for 5 years will be allowed to enter the trial.
9. Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Women / men of childbearing potential not using a reliable contraceptive method (oral contraceptive , other hormonal contraceptive, intrauterine device, diaphragm or condom). (Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential). Patients must agree to continue contraception for 30 days from the date of the last study drug administration.
10. Serious, uncontrolled, concurrent infection(s) requiring IV antibiotics or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy.
11. Uncontrolled hypertension \[blood pressure of \>/=140/90 mmHg on medication\], New York Heart Association (NYHA) Class II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), significant vascular disease (e.g., aortic aneurysm, aortic dissection) or Class II or greater peripheral vascular disease, history of stroke or TIA within 6 months prior to study enrollment, history of hypertensive crisis or hypertensive encephalopathy.
12. History of active angina or myocardial infarction within 6 months. History of significant ventricular arrhythmia requiring medication with antiarrhythmics, or a history of a clinically significant conduction system abnormality.
13. Psychiatric disorders rendering patients incapable of complying with the requirements of the protocol.
14. History or evidence upon physical examination of CNS disease (e.g., primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of stroke)
15. Prior history of pulmonary embolism or deep venous thrombosis.
16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study, other than that defined by protocol; fine needle aspirations or core biopsies within 7 days prior to Day 0.
17. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome or inability to swallow.
18. Known, existing uncontrolled coagulopathy, INR \>/= 1.5.
19. Patients on Coumadin must be changed to Lovenox at least 1 week prior to starting capecitabine. Low dose (1 mg) Coumadin is allowed. Intravenous and low-molecular weight heparin are permitted.
20. Patients taking Sorivudine or Brivudine must be off of these drugs for 4 weeks prior to starting capecitabine. Patients taking cimetidine must have this drug discontinued. Ranitidine or a drug from another anti-ulcer class can be substituted for cimetidine if necessary. If patient is currently receiving allopurinol, must discuss with PI to see of another agent may substitute for it.
21. Current serious, nonhealing wound, ulcer, or bone fracture.
22. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0.
23. Patients who have had an organ allograft.
24. Inability to comply with study and/or follow-up procedures.