Ph 3 ADI-PEG 20 Versus Placebo in Subjects With Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic Therapy

A Randomized, Double-Blind, Multi-Center Phase 3 Study of ADI-PEG 20 Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Subjects With Advanced Hepatocellular Carcinoma (HCC) Who Have Failed Prior Systemic Therapy

This is a study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme versus placebo in patients with hepatocellular carcinoma who have failed prior systemic treatment (chemotherapy). Hepatocellular carcinomas have been found to require arginine, an amino acid. Thus the hypothesis is that by restricting arginine with ADI-PEG 20, the hepatocellular carcinoma cells will starve and die.

Patients will be randomized 2:1 to study drug versus placebo. Patients will be recruited from North American, Europe and Asia. In addition to overall survival, progression free survival, responses by RECIST 1.1 criteria and time to tumor progression will be calculated. Safety and tolerability will be assessed, as will pharmacodynamics (peripheral blood levels of arginine and citrulline), pharmacokinetics (peripheral blood levels of ADI-PEG 20) and immunogenicity (antibodies to ADI-PEG 20).

Inclusion Criteria:

• Prior diagnosis of HCC confirmed histologically.
• Prior treatment with at least 1 systemic agent, with documented progressive disease after systemic agent(s), or adverse event(s)associated with prior systemic agent(s) that resulted in discontinuance of that agent(s).
• Cirrhotic status of Child-Pugh grade B7.
• Expected survival of at least 3 months.
• Adequate hematologic, hepatic, and renal function.

Exclusion Criteria:

• Candidate for potential curative therapies (i.e., resection or transplantation) or loco-regional approaches (i.e., ablation, embolization).
• Significant cardiac disease.
• Serious infection requiring treatment with systemically administered antibiotics.
• Pregnancy or lactation.
• Expected non-compliance.
• Uncontrolled intercurrent illness, or psychiatric illness or social situations that would limit compliance with study requirements.
• Subjects who have had any anticancer treatment within 2 weeks prior to entering the study.
• Subjects who have not fully recovered from toxicities associated with previous HCC loco-regional or systemic therapies.
• Subjects with history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the investigator will not affect patient outcome in the setting of current HCC diagnosis.
• Allergy to pegylated products.
• Bleeding esophageal or gastric varices within the prior three months, except if banded or treated.
• Subjects known to be HIV positive.
• Uncontrolled ascites (defined as not easily controlled with diuretic treatment).
• Having received any blood transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony stimulating factors (G-CSF) within 7 days prior to screening laboratories or after screening laboratories have been obtained until first dose of study drug or placebo.
• Use of traditional medicines approved by local authorities, including but not limited to Chinese herbs within 14 days of first dose of study drug or placebo.
• ECOG performance status > 2.
• Prior allograft,including liver transplant.