Everolimus and Pasireotide (SOM230) in Patients With Advanced or Metastatic Hepatocellular Carcinoma

This open label, single-arm Phase II study will assess time to progression (TTP) and safety
of everolimus and pasireotide in patients with advanced or metastatic hepatocellular
carcinoma (HCC) and limited prior systemic therapy. Should this regimen demonstrate
efficacy, this will support a Phase III randomized clinical trial of this combination
therapy. At least 30 patients will be enrolled into this Phase II study. Additionally, given
the potential importance of the RAS/RAF/MEK/ERK and RAS/pAKT pathways, we propose to
correlate outcomes with baseline pAKT, p-S6, somatostatin receptor tumor expression, and
serum VEGF expression. We anticipate these exploratory analyses will increase understanding
of the molecular pathways and their inhibition in this disease. The study will be performed
as a University of North Carolina-coordinated, multicenter study.

Inclusion Criteria:

- Each subject must meet all of the following inclusion criteria to participate in this
study:

1. Advanced or metastatic hepatocellular carcinoma (stage C per the BCLC criteria,
see Appendix A). HCC may be diagnosed by tissue diagnosis or Alpha-fetoprotein
(AFP) >400 ng/mL with compatible mass on Magnetic Resonance Imaging Scan (MRI).
Cat Scan (CT) abdomen with 3-phase contrast with arterial phase enhancement is
acceptable, although MRI is preferred (imaging should be done within 4 weeks of
study initiation). Recurrences of previously resected HCC will not require
tissue confirmation if there is clear radiographic recurrence in the judgment of
the investigator. Disease must not otherwise be amenable to local therapy.

2. Maximum Childs-Pugh score 6 (see Appendix A) with no active encephalopathy

3. Prior systemic therapy limited to sorafenib that was discontinued due to
intolerance. Patients must undergo at least a 4-week washout prior to
enrollment.

4. Eastern Cooperative Oncology Group (ECOG) PS of 0-2

5. Life expectancy of >12 weeks

6. Age ≥18 years

7. Patients who have received previous local therapy, such as surgery,
radiotherapy, hepatic arterial embolization, chemoembolization, radiofrequency
ablation, percutaneous injection, or cryoablation, will be eligible for
enrollment in the study provided that there is documented progression and
disease is not amenable to further local therapies. Therapy must be completed >4
weeks prior to study initiation (Day 1 of everolimus and pasireotide
administration).

8. Minimum of 4 weeks since any major surgery

9. No active serious infection or other comorbid illness which would impair ability
to participate in the trial.

10. International Normalized Ratio (INR) ≤1.5. (Anticoagulation is allowed if target
INR ≤2.0 on a stable dose of warfarin or on a stable dose of low molecular
weight heparin (LMWH) for >2 weeks at time of enrollment).

11. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides
(TGs) ≤2.5 x upper limit of normal (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.

12. Patients must have adequate organ function as evidenced by:

- Absolute neutrophil count (ANC) ≥1.5 x 109/L

- Platelet count ≥50 x 109/L

- Hemoglobin (Hg) >9 g/dL

- Bilirubin ≤2 x ULN

- Aspartate transaminase (AST) or Alanine transaminase (ALT) ≤5 x ULN

- Serum creatinine ≤1.5 x ULN OR creatinine clearance ≥50 mL/min (estimated
by Cockcroft Gault or measured)

13. Serum magnesium and serum potassium within institutional normal limits (patients
may be on replacement)

14. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test performed within 7 days prior to Day 1 of everolimus and
pasireotide administration.

15. WOCBP and men must agree to use adequate contraception (barrier method of birth
control) prior to study entry and for the duration of study participation. Men
and women should use adequate birth control for at least 8 weeks after the last
administration of study drugs. (Oral, implantable, or injectable contraceptives
may be affected by cytochrome P450 interactions and are therefore not considered
effective for this study.)

16. Signed, Institutional Review Board (IRB) approved written informed consent

Exclusion Criteria:

- Patients meeting any of the following exclusion criteria at baseline will be excluded
from study participation:

1. Patients who have received prior treatment with an mTOR inhibitor (e.g.,
sirolimus, temsirolimus, everolimus) or somatostatin analog (e.g. octeotride)

2. Chronic treatment with systemic steroids (except for intermittent topical, local
injection, or eye drops) or another immunosuppressive agent. NOTE: This
restriction regarding systemic steroids does not apply should patient need
course of glucocorticoid for treatment of non-infectious pneumonitis during
study (see Section 4.5.2).

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

4. Patients with a known hypersensitivity to somatostatin or to its excipients

5. Concurrent or planned radiation, hormonal, chemotherapeutic, experimental, or
targeted biologic therapy

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

7. 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 (New York Heart Association [NYHA]
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 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 fasting serum glucose >1.5 x ULN or
Glycated hemoglobin (HbA1c) >8.0% (Note: at the principle investigator's
discretion, ineligible patients can be re-screened after adequate medical
therapy has been instituted.)

- Active (acute or chronic) or uncontrolled severe infections. NOTE: A
detailed assessment of Hepatitis B/C medical history and risk factors must
be done at screening for all patients. Hepatitis B viral deoxyribonucleic
acid (HBV DNA) and Hepatitis C viral ribonucleic acid (HCV RNA) polymerase
chain reaction (PCR) testing are required at screening for all patients
with a positive medical history based on risk factors and/or confirmation
of prior HBV/HCV infection. See Section 4.2 for further information.

8. Clinically significant third space fluid accumulation (i.e., ascites requiring
paracentesis despite use of diuretics) or pleural effusion that either requires
thoracentesis or is associated with shortness of breath

9. Risk factors for prolongation of Corrected QT Interval (QTc)* including:

- QTc 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 AV block

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

- Concomitant medication(s) known to increase QT interval (See Appendix B)

- University of North Carolina at Chapel Hill (UNC) uses GE
electrocardiogram (ECG) carts which use the Bazett formula for QTc.

10. Patients should not receive immunization with attenuated live vaccines within 1
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-Guérin (BCG), yellow fever,
varicella, and TY21a typhoid vaccines.

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

12. Symptomatic cholelithiasis

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

14. A known history of HIV seropositivity (HIV testing is not mandatory)

15. 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.)

16. Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
(except warfarin as long as the goal INR is ≤1.5). Low-molecular-weight heparin
(LMWH) is permitted (see Section 3.1.10.)

17. Unable or unwilling to discontinue use of prohibited fruit (or its juices)
and/or prohibited medications listed in Appendix B for at least 14 days or five
half-lives of a drug (whichever is longer) prior to the first dose of study drug
and for the duration of the study

18. 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

19. Active alcohol intake of 80 grams or more per day. For reference, one portion of
alcohol (one glass of wine, one can or bottle of beer, or one ounce of hard
liquor) contains approximately 15 grams of ethanol.

20. Inability to comply with study and/or follow-up procedures

21. History of noncompliance to medical regimens