Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

l. To assess the progression-free survival rate of patients with locally advanced or
metastatic pancreatic neuroendocrine tumors treated with everolimus alone or everolimus plus
bevacizumab.

SECONDARY OBJECTIVES:

I. To compare progression-free survival (PFS) among treatment arms shown to be efficacious.

II. To estimate the overall tumor response rate in patients with metastatic pancreatic
neuroendocrine tumors treated with one of two novel regimens.

III. To estimate the overall biochemical response rate (as measured by plasma chromogranin A
levels) in patients with metastatic pancreatic neuroendocrine tumors treated with these
regimens.

IV. To assess the toxicity of each regimen in patients with metastatic pancreatic
neuroendocrine tumors.

V. To assess the overall survival of patients with pancreatic neuroendocrine tumors treated
with these regimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive everolimus orally (PO) once daily (QD) on days 1-28 and octreotide
acetate intramuscularly (IM) on day 1.

ARM II: Patients receive everolimus and octreotide acetate as in Arm I. Patients also receive
bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 3 years.

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:

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 computed
tomography (CT) scan

- Non-measurable disease:

All other lesions, including small lesions (longest diameter < 20 mm with conventional
techniques or < 10 mm with spiral CT scan) and truly non-measurable 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

- No prior treatment with bevacizumab, everolimus, or other mammalian target of
rapamycin (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

- 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

- 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

- 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-hepatitis B virus (HBV); HBV seropositive patients (hepatitis B
surface antigen [HBsAg] positive) are eligible if they are closely monitored for
evidence of active HBV infection by HBV deoxyribonucleic acid (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 ribonucleic acid [RNA]) is undetectable

- No clinical evidence of brain metastases or carcinomatous meningitis

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

- No history of clinically significant bleeding episodes

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

- No uncontrolled diabetes mellitus

- Patients with a history of severely impaired lung function as defined as
spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is
50% of the normal predicted value and/or oxygen (O2) 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 upper limit of normal (ULN) should initiate
lipid-lowering medications with the goal of achieving levels below these
thresholds

- No history of intolerance or allergies to octreotide

- Patients with a history of hypertension must be adequately controlled (baseline
blood pressure [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

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Women must not be pregnant or lactating; both men and women of childbearing
potential must be advised of the importance of using effective birth control
measures during the course of the study

- Granulocytes >= 1,500/uL

- Platelets >= 100,000/uL

- Creatinine =< 1.5 x upper limit of normal

- Bilirubin =< 1.5 x upper limit of normal

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
upper limit of normal (=< 5 x upper limit of normal if liver metastases present)

- Urine protein =< 1+ OR urine creatinine ratio =< 1 (by urinalysis)

- If urine protein creatinine (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