Study of Pasireotide Long Acting Release (LAR) in Patients With Metastatic Neuroendocrine Tumors (NETs)

This is a multi-institutional, prospective phase II open-label trial.

The investigational drug used in this study is pasireotide LAR 60 mg. Pasireotide will be
administered as an intramuscular injection at the beginning of every cycle which is defined
as 28 days (+/- 3 days). Study treatment should begin within 14 days following enrollment
into the study and continue until disease progression, unacceptable toxicity, or withdrawal
of consent. Safety and efficacy will be assessed throughout the treatment period.

Inclusion Criteria:

- Locally unresectable or metastatic carcinoid or pancreatic neuroendocrine tumors

- Tumors must be considered well or moderately differentiated (or low to intermediate
grade). Patients with poorly differentiated neuroendocrine carcinomas or small cell
carcinomas are excluded from the study.

- No prior systemic antineoplastic neuroendocrine tumor treatment (including prior
somatostatin analogs). However patients who have received a short course of
subcutaneous (SQ) octreotide (<10 days) in the past are eligible if > 1 week has
elapsed from their last octreotide injection.

- Minimum of four weeks since any major surgery

- Measureable disease by Response Evaluation Criteria in Solid Tumors (RECIST)

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

- Life expectancy 12 weeks or more

- Adequate bone marrow function as shown by: absolute neutrophil count (ANC) ≥ 1.0 x
10^9/L, Platelets ≥ 75 x 10^9/L, hemoglobin (Hgb) > 8 g/dL

- Adequate liver function as shown by: serum bilirubin ≤ 2.0 x upper limit of normal
(ULN), and serum transaminases activity ≤ 2 x ULN, with the exception of serum
transaminases (< 3 x ULN) if the patient has liver metastases

- Adequate renal function as shown by serum creatinine ≤ 2.0 x ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x
ULN. Note: In case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication.

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 14 days of the administration of the first study treatment. Women must not be
lactating. Both men and WOCBP must be advised of the importance of using effective
birth control measures during the course of the study.

- Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks by the
investigator (or his/her designee) with the aid of written information.

Exclusion Criteria:

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Patients with prior or concurrent malignancy except for the following: adequately
treated basal cell or squamous cell skin cancer, or other adequately treated in situ
cancer, or any other cancer from which the patient has been disease free for 5 years

- Patients with uncontrolled diabetes mellitus or a fasting plasma glucose > 1.5 ULN or
glycosylated hemoglobin (HbA1c) >8%. Note: At the principle investigator's discretion,
non-eligible patients can be re-screened after adequate medical therapy has been
instituted.

- Patients with symptomatic cholelithiasis

- Patients who have congestive heart failure: New York Heart Association (NYHA) Class
III or IV, unstable angina, or a history of acute myocardial infarction within the 6
months preceding enrollment

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Severely impaired lung function

- Any active (acute or chronic) or uncontrolled infection/ disorders

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

- Known hypersensitivity to somatostatin analogues or any component of the pasireotide
LAR formulation

- Corrected QT interval (QTcF) of >470 msec on screening Electrocardiogram (ECG)

- Risk factors for Torsades de Pointes such as cardiac failure, clinically
significant/symptomatic bradycardia

- Clinically significant hypokalemia or hypomagnesemia that are not correctable

- History of sustained ventricular tachycardia, ventricular fibrillation, advanced heart
block, or idiopathic syncope thought to be related to ventricular arrhythmia

- Concomitant medication(s) known to increase the QT interval

- History of noncompliance to medical regimens or unwillingness to comply with the
protocol