This is a multicenter, multinational, phase 3, double-blind (subject, caregiver, investigator, outcomes assessor), placebocontrolled trial. Subjects will be randomly assigned on a 3:2 basis in a blinded fashion to aDi-PeG 20 or placebo; 600 evaluable subjects, 400 for aDi-PeG 20 and 200 for placebo will be targeted to detect a 40% improvement with aDi-PeG 20 treatment in overall survival time after first line therapy with 93% power and 0.05 alpha.
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 >= 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 and B7. Subjects on anti-coagulants are to receive only 1 point for their INR status. 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 >= 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 prior major surgery and none within 2 weeks prior to first dose
of study drug or placebo. Liver biopsy for HCC confirmation is allowed.
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 <3.0 mg/dL and no evidence of bile obstruction.
13. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<=5 x upper limit of normal range.
14. Absolute neutrophil count (ANC) >1,500/[MICRO-SYMBOL]L.
15. Platelets >50,000/[MICRO-SYMBOL]L.
16. Serum uric acid <= 8 mg/dL (with or without medication control).
17. 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
>= 60 mL/min.
18. Serum albumin level >= 2.8 g/dl.
19. Prothrombin time (PT)-international normalized ratio (INR): PT <6 seconds above
control or INR <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.
22. Encephalopathy x none or mild (grade 1 or 2, by Child-Pugh classification); lactulose of other
supportive care allowed.
23. Ascites x absent or slightly (by Child-Pugh classification); diuretic therapy allowed.