A Phase II Trial of OSI-906 and Sorafenib in Advanced Hepatocellular Cancer

The purpose of the trial is first to evaluate the safety of the combination of OSI-906 and
sorafenib in patients with hepatocellular cancer (HCC). Patients will be treated in groups of
three with full dose sorafenib and OSI-906. If we do not observe any significant side
effects, then three additional patients will be treated at the same dose level. After
confirming the safety of the combination (possibly after first six patients) the study will
proceed with regular accrual. The patients will receive the treatments orally and will be
evaluated by physical exam, blood work and imaging. If the cancer is well controlled and the
therapy is well tolerated then patients will continue on the trial. If the side effects are
significant or the tumor starts to grow or the patients wishes to stop therapy the patient at
that time will be taken off trial.

The trial will collect blood samples to evaluate the level of the investigational agent in
the blood. Also samples of the patients tumor will be analyzed to evaluate for markers that
may predict who benefits from treatment.

Inclusion Criteria:

- Patients with measurable, histological diagnosis of HCC and whose disease is not
amenable to surgical or regional therapy.

- Prior allowed therapy: surgery, regional therapy (if more than 6 weeks have elapsed
from therapy and if there is an indicator lesion outside the treated area or if there
is clear evidence of progression in the treated lesion), or adjuvant sorafenib (if
disease relapsed more than 6 months after completion of adjuvant therapy).

- Patient with cirrhosis must have Childs-Pugh score of either A or B7.

- Performance status of 0-2.

- Organ function requirements: hemoglobin > 9.0mg/dl; granulocyte count > 1,000 /mm³ ,
platelets > 40,000/mm³ , alanine aminotransferase (ALT)/aspartate aminotransferase
(AST) up to 5 times the institutional upper limit of normal, alkaline phosphatase < 4
times the institutional upper limit of normal and serum creatinine < 2mg/dl.

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

- Patients - both males and females - with reproductive potential (ie, menopausal for
less than 1 year and not surgically sterilized) must 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 registration.

Exclusion Criteria:

- Patients with mixed histology or fibrolamellar variant.

- Fasting glucose >150 mg/dl and any prior history of diabetes.

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

- Prior systemic therapy for metastatic disease.

- Corrected QT (QTc) interval > 450 msec at baseline.

- Concomitant drugs that prolong the QTc interval.

- Significant cardiac disease defined as: congestive heart failure (NYHA class 2 or
higher) or active coronary artery disease (MI within 6 months of study enrollment).

- Pregnant or breast-feeding females.

- Serious active infections.

- Encephalopathy.

- Uncontrolled ascites defined as symptomatic ascites not controlled with diuretic
treatments.

- Active second primary malignancy except for is situ carcinoma of the cervix or
adequately treated basal cell carcinoma of the skin within less than one year of
enrollment into the study.

- Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are
prohibited within 14 days prior to enrollment.

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

- Patients with a history of poorly controlled gastrointestinal disorders that could
affect the absorption of study drug (e.g., Crohn's disease, ulcerative colitis, etc).