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)].