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
The primary objective of this study is to assess overall survival. The secondary objectives of this study are to: - Assessment of safety and tolerability - Assessment of progression-free survival (PFS), tumor response rate by RECIST (1.1)criteria and time to progression (TTP)
INCLUSION CRITERIA A subject will be eligible for study participation if he/she meets the following criteria: 1. Prior diagnosis of HCC confirmed histologically or cytologically. 2. Prior treatment with at least 1 systemic agent, with documented PD after systemic agent(s), or AEs associated with prior systemic agent(s) that resulted in discontinuance of that agent(s). Failure is defined as having progressed radiographically on, or been intolerant to prior systemic therapy. Intolerance is defined as discontinuation due to an AE(s) on prior systemic therapy that was unacceptable to the treating physician and / or patient, with or without dose interruption and modification. For sorafenib or any other systemic antineoplastic agent, failure requires at least 14 days of treatment for the agent that defines failure, except for a subject that has a severe allergic reaction to the prior systemic agent at any time, even less than 14 days of treatment of that agent and thus it would be imprudent to re-challenge them with that agent. 3. Measurable disease using RECIST 1.1 criteria (Appendix A). At least 1 measurable lesion must be present. Subjects who have received local-regional therapy such as(but not limited to) chemoembolization, embolization, cryoablation, hepatic artery therapy, percutaneous ethanol injection, radiation therapy, radiofrequency ablation or surgery are eligible, provided that they have either a target lesion which has not been treated with local therapy and/or the target lesion(s) within the field of the local-regional therapy has shown an increase of ï¿½ 20% in size. Local-regional therapy must be completed at least 4 weeks prior to the baseline CT scan. Local therapies including chemoembolization do not count as prior systemic therapy. 4. Cirrhotic status of Child-Pugh grade A. Child-Pugh status should be determined based on clinical findings and laboratory data during the screening period. 5. Expected survival of at least 3 months. 6. Age ï¿½ 18 years. 7. No prior systemic treatment for HCC in the last 2 weeks prior to first dose of study drug or placebo. 8. Fully recovered from any prior surgery and none within 2 weeks prior to first dose of study drug or placebo. 9. Female subjects of childbearing age and male subjects must be asked to use appropriate contraception for both the male and female for the duration of the study. Subjects must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study. Females must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. 10. Informed consent must be obtained prior to study initiation. 11. No concurrent investigational studies are allowed. 12. Total bilirubin less than 3.0 mg/dL and no evidence of bile obstruction. 13. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ï¿½5 x upper limit of normal range. 14. Absolute neutrophil count (ANC) greater than 1,500/Î¼L. 15. Platelets greater than 50,000/Î¼L. 16. Serum uric acid ï¿½ 8 mg/dL (with or without medication control). 17. Serum creatinine ï¿½ 1.5 x the upper limit of normal range, or, if serum creatinine greater than 1.5 x the upper limit of normal range, then the creatinine clearance must be ï¿½ 60 mL/min. 18. Serum albumin level ï¿½ 2.8 g/dl. 19. Prothrombin time (PT)-international normalized ratio (INR): PT less than 6 seconds above control or INR less than 1.7. 20. Subjects with active hepatitis B or C on anti-viremic compounds may remain on such treatment, except for interferon. 21. Brain metastases are allowed if well controlled and without seizures. EXCLUSION CRITERIA A subject will not be eligible for study participation if he/she meets any of the exclusion criteria: 1. Candidate for potential curative therapies (i.e., resection or transplantation) or locoregional approaches (i.e., ablation, embolization). 2. Significant cardiac disease (New York Heart Association Class III or IV). 3. Serious infection requiring treatment with systemically administered antibiotics. 4. Pregnancy or lactation. 5. Expected non-compliance. 6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situations that would limit compliance with study requirements. 7. Subjects who have had any anticancer treatment within 2 weeks prior to first dose of study drug or placebo. 8. Subjects who have not fully recovered from toxicities associated with previous HCC loco-regional or systemic therapies. 9. 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. 10. Subjects who had been treated with ADI-PEG 20 previously. 11. Allergy to pegylated products. 12. History of seizure disorder. 13. Bleeding esophageal or gastric varices within the prior three months, except if banded or treated. 14. Subjects known to be HIV positive. 15. Uncontrolled ascites (defined as not easily controlled with diuretic treatment). 16. Having received any blood transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony stimulating factors (GCSF) within 7 days prior to screening laboratories or after screening laboratories have been obtained until first dose of study drug or placebo. 17. Use of traditional medicines approved by local authorities, including but not limited to Chinese herbs within 2 weeks prior to the first dose of study drug or placebo. 18. Eastern Cooperative Oncology Group (ECOG) performance status greater than 2.
This is a multi-center, multi-national, phase 3, double-blind (subject, caregiver, investigator, outcomes assessor), placebo-controlled trial of ADI-PEG 20 in subjects with advanced HCC who have failed prior systemic therapy. Eligible subjects will receive ADI-PEG 20 at 160 IU/m2 (18 mg/m2) or placebo by intramuscular (IM) injection (1 cycle equal to 4 weekly treatments). Subjects in both groups will continue to receive best supportive care. CT (or Magnetic Resonance Imaging [MRI]) scans will be performed at baseline and at the end of every 12 weeks (3 cycles) for assessment of tumor response.
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