Study of Lanreotide in Patients With Metastatic Gastrointestinal Neuroendocrine Tumors Who Are Undergoing Liver-directed Radioembolization With Yttrium-90 Microspheres

This is an open-label, prospective, multi-center Phase II study for patients with metastatic
well-to-moderately differentiated neuroendocrine tumors, including typical carcinoid and
pancreatic neuroendocrine tumors, who are candidates for liver-directed radioembolization.

Lanreotide (Somatuline® Depot) Injection, is FDA-approved for treating unresectable, well- or
moderately-differentiated, locally advanced or metastatic gastroentero-pancreatic
neuro-endocrine tumors (GEP-NETs) to improve progression-free survival. Radioembolization
with yttrium-90 microspheres (SIR-Spheres® therapy) is FDA-approved for treating liver
metastases from colorectal cancer. While each of these individual treatments has had
promising results, investigators hypothesize that treatment for patients with NETs can be
optimized by co-administration of both therapies. Patients will receive treatment with
lanreotide (120 mg subcutaneously every 28 days) in combination with SIR-Spheres therapy. The
dose and treatment day of SIR-Spheres will be determined by the treating radiation
oncologist. Patients who are currently receiving or have previously received lanreotide are
eligible, and treatment with lanreotide can continue monthly until disease progression or
unacceptable toxicity. Up to 25 patients are planned for enrollment to be conducted at
approximately 5 investigational sites in the U.S.

Inclusion Criteria:

- Metastatic well-to-moderately differentiated (or low-grade) neuroendocrine carcinoma,
including typical carcinoid or pancreatic islet cell carcinoma.

- Computerized tomography (CT) scan evidence of liver metastases which are not treatable
by surgical resection or local ablation with curative intent at the time of study
entry. If a CT scan is not possible, then an MRI may be used.

- Patients who are currently receiving or have previously received lanreotide or another
somatostatin analogue are eligible. Previous treatment with lanreotide or another
somatostatin analogue is not required for study entry.

- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

- Adequate hematologic, hepatic and renal function.

- Male patients with female partners of childbearing potential and women patients of
childbearing potential are required to use two forms of acceptable contraception,
including one barrier method, during their participation in the study and for 3 months
(90 days) following last dose of study drug(s). Male patients must also refrain from
donating sperm during their participation in the study and for 3 months after last
dose of study drug(s).

- Life expectancy ≥ 3 months.

- Willingness and ability to comply with study and follow-up procedures.

- Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

- Anti-cancer therapy with the exception of lanreotide or another somatostatin analogue
within 21 days or 5 half-lives (whichever is shorter) of starting study treatment.

- Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
administered ≤28 days or limited field radiation for palliation ≤7 days prior to Cycle
1 Day 1 or has not recovered from side effects of such therapy.

- Major surgical procedures ≤28 days of beginning study drug, or minor surgical
procedures ≤7 days. No waiting required following port-a-cath placement.

- Previously untreated brain metastases. Patients who have received radiation or surgery
for brain metastases are eligible if therapy was completed at least 2 weeks prior to
study entry and there is no evidence of central nervous system disease progression,
mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.

- Clinically significant ascites, cirrhosis, portal hypertension, or thrombosis as
determined by clinical or radiologic assessment.

- Pregnant or lactating.

- Acute or chronic liver, renal, or pancreas disease.

- Any of the following cardiac diseases currently or within the last 6 months:

- Left Ventricular Ejection Fraction (LVEF) <45% as determined by Multiple Gated
Acquisition (MUGA) scan or echocardiogram (ECHO)

- QTc interval >480 ms on screening electrocardiogram (ECG)

- Unstable angina pectoris

- Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2

- Acute myocardial infarction

- Conduction abnormality not controlled with pacemaker or medication

- Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible)

- Valvular disease with significant compromise in cardiac function

- Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] greater than
180 mmHg or diastolic blood pressure (DBP) greater than100 mmHg) (patients with values
above these levels must have their blood pressure (BP) controlled with medication
prior to starting treatment).

- Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular
weight heparin is allowed.

- Serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
treatment.

- Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C. Lab test
results will be confirmed by the treating physician prior to study enrollment using
patient's records not more than 1 year old.

- Presence of other active cancers, or history of treatment for invasive cancer ≤5
years. Patients with Stage I cancer who have received definitive local treatment and
are considered unlikely to recur are eligible. All patients with previously treated in
situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of
non-melanoma skin cancer.

- Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.