Phase II Capecitabine, Oxaliplatin & Bevacizumab for Metastatic / Unresectable Neuroendocrine Tumors

Inclusion Criteria: Subjects must be treated at Stanford University Medical Center for the entire length of study participation.

* Patients must have histologically or cytologically confirmed neuroendocrine tumor, including both well-differentiated tumors (carcinoid) or moderately to poorly differentiated tumors. Patients must be deemed unresectable due to involvement of critical vasculature, adjacent organ invasion, or presence of metastasis.
* Patients with prior surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of \> 5 years has elapsed between the primary surgery and the development of metastatic disease. Clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.
* Prior chemotherapy will be permitted, although the patient may not have had prior oxaliplatin.
* Patients must have a primary or metastatic lesion measurable in at least one dimension by Modified RECIST criteria (see Section 4.2) within 4 weeks prior to entry of study
* Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
* Patients must be ≥ 18 years of age
* Laboratory values ≤ 2 weeks prior to randomization:

  * Absolute Neutrophil Count (ANC) \>=1500/mm3
  * Platelets (PLT) ≥ 100,000/mm3
  * Hemoglobin (Hgb) ≥ 9 g/dL
  * Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
  * Serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if liver metastases present)
  * Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), and alkaline phosphatase ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present). Note: Endoscopic retrograde cholangiopancreatogram (ERCP) or percutaneous stenting may be used to normalize the liver function tests.
* Life expectancy ≥ 12 weeks
* Ability to give written informed consent according to local guidelines

Exclusion Criteria:- Disease-Specific Exclusions

1. Prior oxaliplatin for any reason.
2. Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
3. Prior biologic or immunotherapy ≤ 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities
4. Prior therapy with anti-vascular endothelial growth factor (VEGF) agents
5. If history of other primary cancer, subject will be eligible only if she or he has:

   * Curatively resected non-melanomatous skin cancer
   * Curatively treated cervical carcinoma in situ
   * Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 3 years
6. Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment.

   * General Medical Exclusions

1\. Subjects known to have chronic or active hepatitis B or C infection 2. History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with study participation or study drug administration or may interfere with the conduct of the study or interpretation of study results 3. Male subject who is not willing to use adequate contraception upon enrollment into this study and for 6 months following the last dose of second-line treatment 4. Female subject (of childbearing potential, post-menopausal for less than 6 months, not surgically sterilized, or not abstinent) who is not willing to use an oral, patch or implanted contraceptive, double-barrier birth control, or an intrauterine device (IUD) during the course of the study and for 6 months following the last dose of second-line treatment 5. Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours prior to randomization 6. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea) 7. Any of the following concurrent severe and/or uncontrolled medical conditions within 24 weeks of enrollment which could compromise participation in the study:

* Unstable angina pectoris
* Symptomatic congestive heart failure
* Myocardial infarction ≤ 6 months prior to registration and/or randomization
* Serious uncontrolled cardiac arrhythmia
* Uncontrolled diabetes
* Active or uncontrolled infection
* Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
* Chronic renal disease
* Acute or chronic liver disease (eg, hepatitis, cirrhosis) 8. Patients unwilling to or unable to comply with the protocol 9. Life expectancy of less than 12 weeks 10. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

  * Bevacizumab-Specific Exclusions

    1. Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
    2. Any prior history of hypertensive crisis or hypertensive encephalopathy
    3. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
    4. History of myocardial infarction or unstable angina within 6 months prior to study enrollment
    5. History of stroke or transient ischemic attack within 6 months prior to study enrollment
    6. Known central nervous system (CNS) disease
    7. Significant vascular disease (eg, aortic aneurysm, aortic dissection)
    8. Symptomatic peripheral vascular disease
    9. Evidence of bleeding diathesis or coagulopathy
    10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
    11. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
    12. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
    13. Serious, non-healing wound, ulcer, or bone fracture
    14. Urine protein ≥ 2+ on urinalysis dipstick and ≥ 1.0 gram on 24-hour urine collection
    15. Known hypersensitivity to any component of bevacizumab