Randomized Phase II Study of Everolimus Alone Versus Everolimus Plus Bevacizumab in Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

Inclusion Criteria:

- Patients must have histologic documentation of well-differentiated or moderately
differentiated neuroendocrine tumor from either a primary or metastatic site

- If different histologic classification schemes are used, equivalent histologic
classifications (for example "grade 1", "low-grade", or "intermediate-grade")
are allowed

- Patients with poorly differentiated neuroendocrine carcinoma or small cell
carcinoma are excluded

- Documentation from a metastatic disease site is sufficient if there is clinical
evidence of a pancreatic primary site

- Locally unresectable or metastatic disease

- Patients must have either histologic documentation of a pancreatic primary site, or
clinical evidence of a pancreatic neuroendocrine primary tumor as determined by the
treating physician

- Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a
pancreatic or peripancreatic primary site is strongly suspected are also
eligible

- Patients must have evidence of disease (measurable or non-measurable) with evidence
of progression within the past 12 months

- Measurable disease is defined as lesions that can be accurately measured in at
least one dimension (longest diameter to be recorded) as ≥ 2 cm with
conventional techniques or as ≥ 1 cm with spiral CT scan

- Non-measurable disease is defined as all other lesions, including small lesions
(longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT
scan) and truly nonmeasurable lesions

- Lesions that are considered non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses that are not confirmed and followed by imaging
techniques

- Cystic lesions

- Treatment with somatostatin analogs is a requirement of the study

- Patients receiving octreotide at the time of study entry may continue at the
same dose level for the duration of the study

- Patients not receiving octreotide will initiate treatment according to study
guidelines

- Prior progression on somatostatin analogs or a negative octreotide scan does not
exclude patient participation in this study

- No clinical evidence of brain metastases or carcinomatous meningitis

- ECOG performance status 0-1

- Granulocytes >= 1,500/uL

- Platelets >= 100,000/uL

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Bilirubin =< 1.5 x ULN

- ALT and AST =< 2.5 x ULN (=< 5 x ULN if liver metastases present)

- Urine protein =< 1+ OR urine creatinine ratio < 1 by urinalysis (if UPC ratio is > 1
on urinalysis, then 24-hour urine collection for protein must be obtained and level
must be < 1,000 mg for patient enrollment

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during study treatment

- No concurrent condition resulting in immune compromise, including chronic treatment
with corticosteroids or other immuno suppressive agents

- No active or severe liver disease (e.g., acute or chronic hepatitis, cirrhosis); no
positive anti-HBV; HBV seropositive patients (HBsAg positive) are eligible if they
are closely monitored for evidence of active HBV infection by HBV DNA testing, and
they agree to receive suppressive therapy with lamivudine or other HBV-suppressive
therapy until at least 4 weeks after the last dose of everolimus; patients who are
hepatitis C antibody positive are eligible provided that hepatitis C viral load
(hepatitis C RNA) is undetectable

- No history of GI perforation within 12 months prior to registration

- No history of clinically significant bleeding episodes

- Patients with a history of hypertension must be adequately controlled (baseline BP <
150/90 mm Hg) on antihypertensives

- No current congestive heart failure (New York Heart Association Class II, III, or IV)

- No symptomatic arterial peripheral vascular disease

- No history of aortic aneurysm, aortic dissection, angina, myocardial infarction,
stroke, or other arterial thrombotic events within 6 months of registration

- No uncontrolled diabetes mellitus

- Patients with a history of severely impaired lung function as defined as spirometry
and DLCO that is 50% of the normal predicted value and/or O_2 saturation that is 88%
or less at rest on room air are excluded

- Patients with fasting serum cholesterol >= 300 mg/dL OR >= 7.75 mmol/L AND fasting
triglycerides >= 2.5 X ULN should initiate lipid-lowering medications with the goal
of achieving levels below these thresholds

- No history of intolerance or allergies to octreotide

- No concurrent palliative radiotherapy

- No prior treatment with bevacizumab, everolimus, or other mTOR inhibitors

- Other prior treatments, including but not limited to prior cytotoxic chemotherapy,
alpha interferon, tyrosine kinase inhibitors, external beam radiation therapy, and
radiopeptide therapy are allowed

- There is no limit on the number of prior treatment regimens

- Any prior treatment (with the exception of octreotide) must be completed at
least 4 weeks prior to initiation of treatment

- Prior treatment with embolization or ablative therapies is allowed if measurable
disease remains outside of the treated area

- There is no limit on the prior number of procedures

- Patients should have completed any major surgery ≥ 4 weeks from start of treatment

- Patients must have completed any minor surgery ≥ 2 weeks prior to start of
treatment

- Patients must have fully recovered from the procedure

- Insertion of a vascular access device is not considered major or minor surgery

- Patients should not receive immunization with attenuated live vaccines within one
week prior to registration or during protocol therapy

- Patients on therapeutic anticoagulation are eligible for the study provided that they
are on a stable dose of anticoagulants