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

Inclusion Criteria:

1. Patients must have histologically confirmed pancreatic neuroendocrine tumors that are considered well- or moderately- differentiated
2. Patients must have metastatic or unresectable disease
3. 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.
4. Prior sunitinib and everolimus will be permitted. A wash-out period of 2 weeks is required prior to first dose on this study.
5. Prior liver directed therapies will be permitted (ie. chemoembolization, radioembolization) as long as target lesions in the liver have demonstrated growth since the liver directed treatment.
6. Prior peptide receptor radionuclide therapy (PRRT) will be permitted as long as target lesions in the liver have demonstrated growth since the liver directed treatment.
7. Low-dose aspirin (<= 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease.
8. Patients must have a primary or metastatic lesion measurable in at least one dimension by Modified RECIST criteria v1.1 (see Section 4.2) within 4 weeks prior to entry of study.
9. Patients must have ECOG performance status of 0-2
10. Patients must be >= 18 years of age.

11. Laboratory values <= 2 weeks prior to randomization:

    • Absolute Neutrophil Count (ANC) >= 1.5 x 109/L (>= 1500/mm3)
    • Platelets (PLT) >= 100 x 10^9/L (=> 100,000/mm^3)
    • Hemoglobin (Hgb) >= 9 g/dL
    • Serum creatinine <= 1.5 x 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: ERCP or percutaneous stenting may be used to normalize the liver function tests.
12. Life expectancy >= 12 weeks.
13. Ability to give written informed consent according to local guidelines.

Exclusion Criteria:

Disease-Specific Exclusions

1. Prior bevacizumab, fluoropyrimidines (capecitabine or 5FU) or temozolomide.
2. Poorly differentiated or high grade pancreatic neuroendocrine tumors
3. 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.

4. Diagnosis of another malignancy, unless the patient was diagnosed at least 3 years earlier and has been disease-free for at least 6 months following the completion of curative intent therapy, specifics as follows:

   • Curatively resected non-melanomatous skin cancer
   • Curatively treated cervical carcinoma in situ
   • Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study 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 the last 3 years.
5. Concurrent use of other investigational agents and patients who have received investigational drugs <= 4 weeks prior to enrollment.

6. Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation and or a known deficiency of dihyropyrimidine dehydrogenase.

   General Medical Exclusions

   Subjects meeting any of the following criteria are ineligible for study entry:

7. Inability to comply with study and/or follow-up procedures.
8. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study .
9. Pregnancy (positive pregnancy test) or lactation- breast feeding Lack of of effective means of contraception (men and women) in subjects of child-bearing potential.
10. 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).
11. Known history of HIV, HBV, or HCV

12. Current, ongoing treatment with full-dose warfarin. However patients may be on stable doses of a low molecular weight heparin are allowed (ie. Lovenox).

    Bevacizumab-Specific Exclusions

13. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg).
14. Prior history of hypertensive crisis or hypertensive encephalopathy.
15. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E).
16. History of myocardial infarction or unstable angina within 6 months prior to Day 1.
17. History of stroke or transient ischemic attack within 6 months prior to Day 1.
18. Known CNS metastases
19. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1.
20. History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1.
21. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
22. 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.
23. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.
24. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.
25. Serious, non-healing wound, active ulcer, or untreated bone fracture.
26. Proteinuria: Patients are allowed to have 0, trace, or 1+ protein by urine dipstick or urinalysis to enroll, if >= 2+ must check 24h urine protein and must be < 1g to start study.
27. Known hypersensitivity to any component of bevacizumab.