Study of ADI-PEG 20 Versus Placebo in Subjects with High Arginine Level and Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

1. Prior diagnosis of HCC confirmed by radiology, histology, or cytology.

2. Prior treatment with at least 1 systemic agent for Child-Pugh A subjects. However,Child-Pugh B7 subjects without prior systemic treatment may be enrolled, if they arenot eligible for any approved systemic therapies (e.g., due to financial factors).

3. Plasma arginine ≥ 78 μM at pre-screening visit.

4. Measurable disease using RECIST 1.1 (Appendix A). At least 1 measurable lesion mustbe present. Subjects who have received local-regional therapies are eligible,provided that they have either a target lesion which has not been treated with localtherapy and/or the target lesion(s) within the field of the local regional therapyhas shown an increase of ≥ 20% in size. Local-regional therapy must be completed atleast 4 weeks prior to the baseline CT scan.

5. Child-Pugh (cirrhosis status) score class A-B7 (Appendix C).

6. Barcelona Cancer of the Liver (BCLC) stage C (Appendix B)

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment (Appendix D).

8. Expected survival of at least 3 months.

9. Age >18 years.

10. Fully recovered from prior surgery, radiation, or chemotherapy, and none within 2weeks prior to week 1 visit. Liver biopsy for HCC confirmation is allowed.

11. Female subjects and male subjects must be asked to use appropriate contraception forboth the male and female for the duration of the study and for 35 days after lastdose of ADI-PEG 20/placebo. Male partners of female subjects and female partners ofmale subjects must agree to use two forms of contraception or agree to refrain fromintercourse for the duration of the study if they are of childbearing potential.Females of childbearing potential must not be pregnant at the start of the study,and a serum human chorionic gonadotropin (HCG) pregnancy test must be negativebefore entry into the study. If positive HCG pregnancy test, further evaluation torule out pregnancy must be performed according to GCP before this subject is deemedeligible. Females not of childbearing potential must be post-menopausal (defined ascessation of regular menstrual period for at least 12 months).

12. Informed consent must be obtained prior to study initiation.

13. No concurrent investigational studies are allowed.

14. Total bilirubin < 3.0 mg/dL and no evidence of bile obstruction.

15. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 x upperlimit of normal range.

16. Serum albumin level ≥ 3.0 g/dl.

17. Prothrombin time (PT)-international normalized ratio (INR): PT <3 seconds abovecontrol or INR <1.7.

18. Absolute neutrophil count (ANC) >1,500/µL.

19. Platelets >50,000/µL.

20. Serum uric acid ≤ 8 mg/dL (with or without medication control).

21. Serum creatinine ≤ 1.5 x the upper limit of normal range, or, if serum creatinine >1.5 x the upper limit of normal range, then the creatinine clearance must be ≥ 40mL/min.

22. Subjects with active hepatitis B or C on anti-viremic compounds may remain on suchtreatment, except for interferon.

23. Encephalopathy - none or mild (grade 1 or 2, by Child-Pugh classification);lactulose of other supportive care allowed.

24. Ascites - absent or slight (by Child-Pugh classification); diuretic therapy allowed.

Exclusion Criteria:

1. Candidate for potential curative therapies (i.e., resection or transplantation) oreligible for approved systemic therapies according to the labeling of such drugs.

2. Prior allograft transplantation including liver transplantation.

3. Subjects who have not fully recovered from toxicities associated with previous HCCloco-regional or systemic therapies, except for Grade 1 alopecia.

4. Serious infection requiring treatment with intravenous, systemically administeredantibiotics at the time of study entrance, or an infection requiring systemicantibiotic therapy within 7 days prior to the first dose of study treatment.

5. Pregnancy or lactation.

6. Expected non-compliance.

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure (New York Heart Association ClassIII or IV), cardiac arrhythmia, or psychiatric illness, social situations that wouldlimit compliance with study requirements.

8. Subjects with history of another primary cancer, including co-existent secondmalignancy, with the exception of: a) curatively resected non-melanoma skin cancer;b) curatively treated cervical carcinoma in situ; or c) other primary solid tumorwith no known active disease present or in the opinion of the investigator will notaffect patient outcome.

9. Subjects who had been treated with ADI-PEG 20 previously.

10. History of uncontrolled seizure disorder not related to underlying cancer.

11. Allergy to pegylated compounds.

12. Allergy to E. coli drug products (such as GMCSF).

13. Bleeding esophageal or gastric varices within the prior three months, except ifbanded or treated.

14. Uncontrolled ascites (defined as not easily controlled with diuretic treatment).

15. Having received any blood transfusion, blood component preparation, erythropoietin,albumin preparation, or granulocyte colony stimulating factors (G-CSF) within 7 daysprior to screening laboratories or after screening laboratories have been obtaineduntil week 1 visit.

16. Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2.