safety issue observed on another hepatocellular study using OSI906

The purpose of this study is to evaluate the effect of combining a new investigational drug (OSI-906) with a standard drug (sorafenib) on the control of liver cancer (hepatocellular cancer). Sorafenib (brand name Nexavar®) is a drug that is approved for the treatment of advanced liver cancer. It works by stopping the growth of new blood vessels around the tumor. OSI-906 is an investigational agent that works by inhibiting the effects of a growth hormone on the cancer. The safety and efficacy of combining OSI-906 and sorafenib in the treatment of liver cancer risk not known. The current study will confirm the safety of the combination in the first six patients and evaluate the activity of the combination in patients with advanced liver cancer.

In addition, the study will aim at collecting blood samples from patients to evaluate the level of OSI-906 in patients receiving the combination of the two drugs. The study also will collect samples of the tumor to evaluate for markers that can predict in which patient the combination is effective.

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).

A second trial evaluating OSI906 in hepatocellular cancer was being run in parallel to this trial. There were safety signals in the second trial which led to stopping this trial.