Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

INCLUSION CRITERIA * Histologically-confirmed pancreatic neuroendocrine tumors that are moderately- or well-differentiated * Metastatic or unresectable disease * If prior surgical resection \> 5 years before the development of metastatic disease, a separate (recent) histological or cytological confirmation of metastatic disease is required * If there is substantial clinical ambiguity regarding the nature or source of apparent metastases, clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease * The site of previous radiotherapy, if the only site of disease, has evidence of progressive disease * If prior sunitinib and everolimus has been administered, a 2-week wash-out period is required prior to 1st dose on this study * If prior liver-directed therapies (ie, chemoembolization, radioembolization), target lesions in the liver have demonstrated growth since the liver-directed treatment * If prior peptide receptor radionuclide therapy (PRRT), target lesions in the liver have demonstrated growth since the liver-directed treatment * Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease. * Primary or metastatic tumor lesion measurable in at least 1 dimension, within 4 weeks prior to entry of study. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * ≥ 18 years of age. * Laboratory values as follows, ≤ 2 weeks prior to randomization: * Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L (≥ 1500/mm³) * Platelets (PLT) ≥ 100 x 10e9/L (≥ 100,000/mm³) * Hemoglobin (Hgb) ≥ 9 g/dL * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) * Serum bilirubin ≤ 1.5 x ULN * Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present). Note: endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous stenting may be used to normalize the liver function tests * Urine dipstick or urinalysis for protein, value must be 0, trace, or 1+ protein to enroll. EXCEPTION: if ≥ 2+ must check 24-hour urine protein and must be \< 1 g * Life expectancy ≥ 12 weeks * Ability to give written informed consent according to local guidelines * If any prior therapy-related toxicities, must have recovered from all EXCLUSION CRITERIA Disease-Specific Exclusions * Prior bevacizumab; fluoropyrimidines (eg, capecitabine or 5-fluorouracil, 5FU); or temozolomide * Poorly-differentiated or high-grade pancreatic neuroendocrine tumors * Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment * Diagnosis of another malignancy, unless \> 3 years earlier and has been disease-free for \> 6 months following the completion of curative intent therapy, specific eligibility exceptions as follows: * Curatively-resected non-melanomatous skin cancer * Curatively-treated cervical carcinoma in situ * Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values, if hormonal therapy has been initiated or a radical prostatectomy has been performed * Other primary solid tumor curatively treated with no known active disease present and no treatment administered for \> 3 years * Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment * Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation * Known deficiency of dihydropyrimidine dehydrogenase Bevacizumab-specific Exclusions * Inadequately-controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \> 100 mmHg) * Prior history of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Grade II or greater congestive heart failure * History of myocardial infarction or unstable angina within 6 months prior to Day 1 * History of stroke or transient ischemic attack within 6 months prior to Day 1 * Known central nervous system (CNS) metastases * Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 * History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to Day 1 * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1 * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 * Serious, non-healing wound, active ulcer, or untreated bone fracture * Known hypersensitivity to any component of bevacizumab General Medical Exclusions * Inability to comply with study and/or follow-up procedures * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study * Pregnant or lactating/breast feeding * Lack of effective contraception men or women of child-bearing potential * Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) * Known history of HIV, HBV, or HCV * Current, ongoing treatment with full-dose warfarin. However, patients may be on stable doses of a low-molecular weight heparin are allowed \[eg, (enoxaparin (Lovenox)\].