Phase II Trial of SOM230 in Patients With Unresectable Hepatocellular Carcinoma

For all patients, SOM230 will be given at a starting dose of 60 mg intramuscularly (IM) every 28 days. Dose reduction will be allowed for toxicities which are deemed to be therapy-related. Patients will receive SOM230C (IM) as an outpatient and will be observed for at least 30 minutes for any immediate adverse reactions. Toxicity checks will be done every 2 weeks and laboratory tests every 4 weeks during study therapy). Safety and efficacy will be assessed throughout the treatment period. Toxicities will be graded using the Common Terminology Criteria for Adverse Events, version 4.02.

Therapy will continue for maximum of two years if the patient shows no evidence of disease progression or intolerable toxicity. After completion of all study related therapy patients will complete a 30 day safety follow up visit. Patients who are still benefiting from therapy after two years may continue longer only after discussion between the Principal Investigator (PI) and the drug sponsor.

Inclusion criteria

• Diagnosis of unresectable HCC by either:

• Histopathology or
• Elevated serum Alpha-fetoprotein (AFP) >400 ng/ml and findings on magnetic resonance imaging (MRI) or CT scans characteristic of a primary liver tumor.
• Findings on MRI or CT scans characteristic of a primary liver tumor in patients with cirrhosis
• Tumors at least 1 cm or greater
• Age ≥ 18 years.
• 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).
• Patients may have progressed on sorafenib or refused or were intolerant of sorafenib. A maximum of 2 prior lines of systemic therapy (including chemotherapy or targeted therapy) will be allowed. Prior locoregional therapy such as surgery, radiofrequency ablation or transarterial chemoembolization are also allowed (these will not be counted as systemic therapy), provided that progression has been documented after these therapies, and at least 4 weeks have elapsed since the last therapy.
• Karnofsky performance status (KPS) of 80 or Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy 12 weeks or more.
• Adequate bone marrow function as shown by: Absolute neutrophil count (ANC) ≥ 1.2 x 10^9/L, Platelets ≥ 50 x 10^9/L
• Adequate liver function as shown by: serum bilirubin < 1.5x upper limit of normal (ULN) and serum transaminases activity ≤ 3 x ULN. Serum PT =< 16 seconds.
• Adequate renal function as shown by serum creatinine ≤ 1.5 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 (can start after one day of initiation of lipid lowering drug) of appropriate lipid lowering medication.
• Women of childbearing potential must have a negative serum or urine 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.
• 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.
• Child's A and early Child's B (no more than 7 points on the Child Pugh Classification).
• Measurable disease by CT scan with contrast. If evaluable disease or measurable disease has been previously treated, this must show signs of tumor progression by CT. Measurable disease and evaluable disease will be defined by the RECISTguidelines (see section 9.0).
• Patients with cirrhosis either radiologically or pathology with findings either by CT scan or MRI characteristic of primary liver cancer are eligible.

Exclusion criteria

• Prior octreotide therapy or any somatostatin analog.
• Chronic treatment with systemic steroids or another immunosuppressive agent.
• Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry (ie. within 1 week of signing the informed consent).
• 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 five years.
• Patients with uncontrolled diabetes mellitus (defined as HgA1c > 7% or =8% despite therapy) or a fasting plasma glucose > 1.5 ULN. 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 (NYHA Class III or IV), unstable angina,sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollment.
• Patients who are at high risk for cardiac arrhythmias as defined by any of the following:

• Baseline QTcF > 470 msec
• History of syncope or family history of idiopathic sudden death or long QT syndrome
• 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 block (AV) block
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by uncontrolled diabetes, or Parkinson's disease), HIV, uncontrolled hypothyroidism or cardiac failure
• Concomitant medication(s) known to increase the QT interval (see Appendix II)
• 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).
• 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
• Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of pasireotide). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.
• Known hypersensitivity to somatostatin analogues or any component of the pasireotide or octreotide LAR formulations
• History of noncompliance to medical regimens
• Patients unwilling to or unable to comply with the protocol or unable to give informed consent.
• Patients with baseline Alanine transaminase (ALT) or Aspartate transaminase (AST) > 3x ULN.
• Patients with baseline serum bilirubin > 1.5 x ULN.
• Prothrombin time (PT) > 16 seconds and/or partial thromboplastin time (PTT) > 1.5 x ULN
• History of or current alcohol misuse/abuse within the past 12 months.
• Known gallbladder or bile duct disease, acute or chronic pancreatitis.