Pasireotide, Everolimus and Selective Internal Radioembolization Therapy for Unresectable Hepatic Metastases

Liver metastasis remain a major challenge in the care of patients with Neuroendocrine Tumors
(NET). This study is evaluating the combination of systemic therapies plus radioembolization
for the treatment of liver metastasis from NET. The study allows pancreatic and intestinal
NET that have spread to the liver.

Inclusion Criteria:

1. Confirmed low to intermediate grade neuroendocrine tumors with unresectable liver
metastasis

2. Patients must have evidence of disease progression by Response Evaluation Criteria in
Solid Tumors (RECIST) despite optimal octreotide therapy (octreotide long acting
release [LAR] 30 mg every month)

3. Prior treatment permitted include: surgery, prior systemic therapies (≤ 2 prior lines
of chemotherapy), or radiation therapy

4. Patients must have measurable disease by RECIST 1.1 criteria

5. For the patients in the phase Ib study, neuroendocrine tumor must involve both liver
lobes

6. Minimum of four weeks since any major surgery, completion of radiation, or completion
of all prior systemic anticancer therapy (adequately recovered from the acute
toxicities of any prior therapy)

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

8. Adequate bone marrow function as shown by:

- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L

- Platelets greater than or equal to 100 x 10^9/L

- Hb greater than 9 g/dL

9. Adequate liver function as shown by:

- Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN (≤
3x ULN in patients with liver metastases)

10. International normalized ratio (INR) ≤ 1.5 (anticoagulation is allowed if target INR ≤
1.5 on a stable dose of warfarin)

11. Patient receiving low molecular weight (LMW) heparin on stable therapeutic dose for
more than 2 weeks or with factor Xa level < 1.1 U/mL can be enrolled if LMW heparin
can be safely discontinued at least 24 hours prior to invasive vascular procedures
(angiography and SIR-sphere administration)

12. Adequate renal function: serum creatinine ≤ 1.5 x ULN

13. 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.

14. Women of childbearing potential 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 women of childbearing potential must be advised of the importance of
using effective birth control measures during the course of the study.

15. 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:

1. Evidence of ascites, cirrhosis, portal hypertension or portal vein thrombosis

2. Prior radiation to the upper abdomen

3. Contraindications to angiography

4. Patients with extensive tumor replacement of the liver defined as tumor volume > 50%
of liver

5. Lung shunt ≥ 20%

6. Prior treatment with any investigational drug within the preceding 4 weeks

7. Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

8. Patients should not receive immunization with attenuated live vaccines within one week
of study entry or during study period. Close contact with those who have received
attenuated live vaccines should be avoided during treatment with everolimus. Examples
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines.

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

10. Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin

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

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

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function as defined as spirometry and diffusing capacity
of lung for carbon monoxide (DLCO) that is 50% of the normal predicted value
and/or 02 saturation that is 88% or less at rest on room air

- Uncontrolled diabetes as defined by hemoglobin A1C (HbA1c) > 7% despite therapy.

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C)

12. History of liver disease such as cirrhosis or chronic active hepatitis. Presence of
Hepatitis B surface antigen (HepBSAg) or presence of hepatitis C antibody. History of,
or current alcohol misuse/abuse within the past 12 months

13. Patients with the presence of active or suspected acute or chronic uncontrolled
infection or with a history of immunocompromise, including a positive HIV test result
(ELISA and Western blot)

14. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

15. Patients with an active, bleeding diathesis

16. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Adequate contraception
must be used throughout the trial and for 8 weeks after the last dose of study drug,
by both sexes. (Women of childbearing potential [WOCBP] must have a negative urine or
serum pregnancy test within 14 days prior to administration of pasireotide and
everolimus) Oral, implantable, or injectable contraceptives may be affected by
cytochrome P450 interactions, and are therefore not considered effective for this
study.

17. Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment

18. Patients who have received prior treatment with an mammalian target of rapamycin
(mTOR) inhibitor (e.g., sirolimus, temsirolimus, everolimus).

19. Patients with a known hypersensitivity to everolimus or other rapamycins (e.g.,
sirolimus, temsirolimus) or to its excipients

20. Known hypersensitivity to somatostatin analogues or any component of the pasireotide
or octreotide LAR formulations

21. History of noncompliance to medical regimens

22. Patients unwilling to or unable to comply with the protocol

23. QT related exclusion criteria include:

- QT Fridericia's Correction Formula (QTcF) at screening > 450 msec

- History of syncope or family history of idiopathic sudden death

- Sustained or clinically significant cardiac arrhythmias

- Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade
atrioventricular (AV) block

- Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused
by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism
or cardiac failure

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

24. Known gallbladder or bile duct disease, acute or chronic pancreatitis