Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery

PRIMARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of
pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in
disease free survival.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of
pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in
overall survival.

II. To evaluate the toxicity associated with adjuvant everolimus following resection in
patients with metastatic pancreatic neuroendocrine tumors to the liver.

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

ARM A: Patients receive everolimus orally (PO) once daily (QD) on days 1-28. Treatment
repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

ARM B: Patients receive placebo PO QD on days on days 1-28. Treatment repeats every 28 days
for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have histologically or pathologically confirmed metastatic low or
intermediate grade pancreatic neuroendocrine tumor(s) to the liver as per the Klimstra
guidelines

- Patients must have recovered from an R0 or R1 resection of all disease (including
resection of a primary primitive neuroectodermal tumor [PNET] if present); patients
may have had resection plus microwave or radiofrequency ablation, provided that no
ablated lesion was >= 5 cm prior to ablation

- Patients must be within 4 to 8 weeks from the completion of surgery at time of
randomization

- Patients must have paraffin-embedded fixed metastatic tumor tissue available for
submission for central review; core biopsy or surgical specimens required

- Patients must have post-operative computed tomography (CT) or magnetic resonance
imaging (MRI) prior to randomization and =< 4 weeks after completion of surgery to
confirm disease status; patients must be able to tolerate CT or MRI imaging including
contrast agents as required for the protocol

- Patients must NOT have either clinically apparent central nervous system metastases or
carcinomatous meningitis =< 6 months prior to randomization

- Women must NOT be pregnant or breast-feeding; all females of childbearing potential
must have a blood test within 2 weeks prior to randomization to rule out pregnancy

- Women of child-bearing potential and sexually active males must be strongly advised to
use an accepted and highly effective method of contraception or abstain from sexual
intercourse for the duration of their treatment through 8 weeks after their last dose
of protocol therapy; women of child-bearing potential, sexually active males, and the
female partners of male participants should be advised of the risk of becoming
pregnant or fathering a child while receiving protocol treatment; should a woman
become pregnant while participating in this study, she should inform her treating
physician immediately; if a man impregnates a woman while participating in this study,
he should inform his treating physician immediately

- Prior treatment with sunitinib and/or cytotoxic chemotherapy are allowed provided last
dose was > 30 days prior to randomization

- Prior chemoembolization is allowed provided last dose was > 30 days prior to
randomization

- Patients must NOT have received prior everolimus

- Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 X institutional ULN

- Serum creatinine =< 1.5 X institutional ULN or creatinine clearance >= 60 mL/min for
patients with creatinine levels above 1.5 X institutional normal

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x ULN

- Absolute neutrophil count >= 1,500/mm^3

- Leukocytes >= 3,000/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Patients must NOT have ongoing cardiac dysrhythmia of National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) grade >= 2,
uncontrolled atrial fibrillation of any grade, or corrected QT (QTc) interval > 470
msec

- Patients with a history of the following within =< 12 months of randomization are not
eligible

- Arterial thromboembolic events

- Unstable angina

- Myocardial infarction

- Patients must NOT have experienced thrombotic events (deep vein thrombosis, pulmonary
embolism) =< 3 months prior to randomization

- Patients must NOT have liver disease such as cirrhosis, chronic active hepatitis, or
chronic persistent hepatitis at randomization; patients at increased risk for
hepatitis B or hepatitis C must be screened for hepatitis prior to randomization

- Patients must NOT have history of severely impaired pulmonary function for their age;
patients with known history of abnormal pulmonary function must have documentation of
diffusing capacity of the lung for carbon monoxide (DLCO) of > 50% predicted and
oxygen saturation (SaO2) of > 87% at rest on room air =< 4 weeks prior to
randomization

- Patients with unexplained pulmonary infiltrates must have pulmonary function tests
within the institutional limits of normal =< 4 weeks prior to randomization

- Patients with known history of human immunodeficiency virus (HIV) seropositivity are
ineligible

- Patients with poorly controlled diabetes mellitus as defined by hemoglobin A1c (HbA1c)
> 8% despite adequate therapy are ineligible; patients with a known history of
impaired fasting glucose or diabetes mellitus must have blood glucose and antidiabetic
treatment monitored closely throughout the trial and adjusted as necessary

- Patients must NOT have any severe and/or uncontrolled medical conditions such as:

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction =< 6 months prior to randomization, serious uncontrolled cardiac
arrhythmia, or any other clinically significant cardiac disease

- Symptomatic congestive heart failure of New York Heart Association class III or
IV

- Active (acute or chronic) or uncontrolled severe infection, liver disease such as
cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable
hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B
surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid
[RNA])

- Active, bleeding diathesis

- Patients must NOT have previous or concurrent malignancy; exceptions are made for
patients who meet any of the following conditions:

- Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in
situ); OR

- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years

- Patients may not be receiving any other investigational agents while on study
treatment; prior treatment with other investigational agent is allowed provided last
dose was >= 30 days prior to randomization

- Patients must NOT have received live attenuated vaccines =< 1 week prior to
randomization; patients should also be advised not to receive live attenuated vaccines
during the study and to avoid close contact with others who have received live
attenuated vaccines; examples of live attenuated vaccines include intranasal
influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow
fever, varicella and TY21a typhoid vaccines

- Patients must NOT be on chronic treatment with corticosteroids or other
immunosuppressive agents; topical or inhaled corticosteroids are allowed

- Patients should be advised to avoid drugs or foods that are known potent cytochrome
P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers

- Patients must NOT have history of allergic reactions attributed to compounds of
similar chemical or biologic composition to everolimus

- Patients must NOT have known intolerance or hypersensitivity to everolimus or other
rapamycin analogs (e.g. sirolimus, temsirolimus)

- Patients must NOT have absorption issues that would limit the ability to absorb
everolimus

- Patients must NOT have a history of non-compliance to medical regimens or who are
considered potentially unreliable or will not be able to complete the entire study

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Patients must have life expectancy >= 12 weeks