A Randomized, Placebo-controlled, Double-blind Phase 2 Study With OSI-906 in Patients With Advanced HCC

Adult patients with advanced HCC previously treated with sorafenib will be randomized 2:1 to
receive either single agent OSI-906 or placebo

Inclusion Criteria:

- Histologically confirmed diagnosis of advanced HCC. Clinical diagnosis by American
Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients is
acceptable. For patients without cirrhosis histological confirmation is mandatory

- Patients must have received prior systemic treatment for advanced HCC with sorafenib
and had confirmed disease progression or had discontinued sorafenib due to a drug
related toxicity

- Patient has received their last dose of sorafenib at least 14 days prior to
randomization

- Patient has recovered from sorafenib or investigational agent related toxicity to ≤
grade 2

- Measurable disease according to RECIST (version 1.1)

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 - 1

- Child-Pugh Status A or B(7)

- Barcelona Clinic Liver Cancer (BCLC) stage B/C

- Previous local therapy (eg, surgery, radiation therapy, hepatic arterial therapy,
chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or
cryoablation) is permitted if ≥ 21 days before randomization

- Fasting glucose ≤ 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic oral
antihyperglycemic therapy is permitted if the dose has been stable for ≥ 4 weeks at
the time of randomization

- Following laboratory parameters (determined by laboratory):

- Platelets ≥ 60 x 10^9/L

- Hemoglobin ≥ 8.5 g/dL

- Absolute neutraphil count (ANC) ≥ 1.5 x 10^9/L

- Potassium within normal limits (supplementation may be used)

- Partial thrombopastin time (PTT) ≤ 2.3 x Upper Limit of Normal (ULN)

- Magnesium within normal limits (supplementation may be used)

- Calcium within normal limits (supplementation may be used)

- Adequate organ function (for a HCC population):

- Liver function test (LFT) ≤ 5 x ULN

- Albumin ≥ 2.8 g/dL

- Total bilirubin ≤ 2.8 mg/dL

- Creatinine ≤ 1.5 x ULN

- International normalized ratio (INR) ≤ 2.3

- Estimated life expectancy ≥ 12 weeks based on an investigator assessment of recent
changes in laboratory values, performance status, and other clinical criteria

- Patients, both males and females, with reproductive potential (ie, menopausal for less
than 1 year and not surgically sterilized) must agree to practice effective
contraceptive measures throughout the study. Women of childbearing potential must
provide a negative pregnancy test (serum or urine) within 14 days prior to
randomization

- Patients must provide written informed consent to participate in the study

- Prior radiation therapy is permitted provided patients have recovered from the acute,
toxic effects of radiotherapy prior to randomization. A minimum of 21 days must have
elapsed between the end of radiotherapy and randomization; and

- Prior surgery is permitted provided that the surgery was done ≤ 28 days prior to
randomization and adequate wound healing has occurred prior to randomization

Exclusion Criteria:

- Child-Pugh B (8 - 9) or C

- Patients who are candidates for potentially curative intervention (ie, surgical
resection or transplantation)

- Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring
insulinotropic or insulin therapy

- Prior insulin-like growth factor - 1 receptor (IGF-1R) therapy

- Patients requiring interferon

- Patients with uncontrolled symptomatic ascites

- Prior investigational agent within 21 days prior to randomization

- History of poorly controlled gastrointestinal disorders that could affect the
absorption of study drug (eg, Crohn's disease, ulcerative colitis, etc)

- History of organ allograft including liver transplant

- Malignancy other than HCC within the past 3 years:

- Exceptions: resected basal cell or squamous cell carcinoma of the skin, cured in
situ cervical carcinoma, cured ductal carcinoma in situ of the breast, and/or
cured superficial bladder cancer

- History (within last 6 months) of significant cardiovascular disease unless the
disease is well-controlled. Significant cardiac disease includes second/third degree
heart block; clinically significant ischemic heart disease; superior vena cava (SVC)
syndrome; poorly controlled hypertension; congestive heart failure of New York Heart
Association (NYHA) Class II or worse (slight limitation of physical activity;
comfortable at rest, but ordinary physical activity results in fatigue, palpitation,
or dyspnea)

- History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is
symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or
asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial
fibrillation controlled by medication are not excluded

- QTcF interval at screening ≥ 450 msec

- Use of drugs that have a known risk of causing Torsades de Pointes (TdP) ('Torsades
List' on www.azcert.org/medical-pros/drug-lists/by category.cfm)are prohibited within
14 days prior to randomization

- Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent
CYP1A2 inhibitors/inducers are not excluded

- History of cerebrovascular accident (CVA) within 6 months prior to randomization or
that resulted in ongoing neurologic instability

- Active infection or serious underlying medical condition (including any type of active
seizure disorder within 12 months prior to randomization) that would impair the
ability of the patient to receive study drug

- History of human immunodeficiency virus (HIV) infection or acquired immune deficiency
syndrome (AIDS)-related illness or serious acute or chronic illness

- History of any psychiatric or neurologic condition that might impair the patient's
ability to understand or to comply with the requirements of the study or to provide
informed consent

- Pregnant or breast-feeding females

- Symptomatic brain metastases that are not stable, require steroids, are potentially
life threatening, or that have required radiation within 28 days prior to
randomization; and/or

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drug