Efficacy Study of Pegylated Recombinant Human Arginase 1 as a Second-line Therapy in Patients With Advanced Liver Cancer

A Phase II Trial of PEG-BCT-100 as the Second-line Therapy Following Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The purpose of the study is to evaluate the efficacy and safety of PEG-BCT-100 as the second-line therapy following sorafenib in advanced HCC patients. Another objective of the study is to explore whether the expression of OTC and ASS are predictive biomarkers for drug response and prognosis.

This is a phase II, single-arm clinical trial. Approximately 35 subjects will be enrolled in the study. All subjects will be treated with PEG-BCT-100 2.7 mg/kg weekly (day1, 8 and 15). Three week treatment of PEG-BCT-100 is considered as 1 cycle. All subjects will receive PEG-BCT-100 till progressive disease, intolerable toxicity or patients withdraw consent.

The clinical effects of PEG-BCT-100 on disease response will be evaluated every 6 weeks until disease progression. Disease response evaluation will be based on RECIST 1.1 criteria. The disease response based on modified RECIST criteria will also be evaluated and documented for reference only.

Safety parameters will be evaluated throughout the study. Adverse event (AE) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTC AE v4).

All subjects will undergo a tumor tissue biopsy at baseline for evaluation of the biomarkers of ornithine transcarbamylase (OTC) and arginine succinate synthetase (ASS) except for those subjects whose tumor tissue blocks have been obtained within 1 year and are available for the biomarkers evaluation. The association between the levels of the 2 biomarkers and disease response to PEG-BCT-100 treatment will be explored in the study.

The effects on patients' quality of life will be evaluated every 2 cycles of the PEG-BCT-100 treatment.

Inclusion Criteria:

• Clinical diagnosis of hepatocellular carcinoma (HCC) according to the European Association for the Study of the Liver (EASL) criteria
• Patients with advanced HCC defined as unresectable disease which is not amenable OR refractory to local-regional therapy OR with extra-hepatic involvement
• Patients have received prior systemic treatment with sorafenib for at least 14 days (not necessarily consecutive), and resulted in either disease progression or intolerance with sorafenib treatment
• Sorafenib must be the last antineoplastic treatment before enrollment
• Patients who are suitable for percutaneous tissue biopsy
• ECOG Performance Status 0-2
• Adequate hematological, renal and hepatic function as assessed by the following blood tests sampled at screening visit
• Life expectancy longer than 12 weeks
• Subjects with at least one measurable lesion assessed by CT scan or other imaging within 4 weeks prior to the first dose of PEG-BCT-100
• Normal ECG
• Patients who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.

Exclusion Criteria:

• Has received any surgery, loco-ablative, transarterial therapy or radiotherapy ≤ 2 weeks prior to the first dose of PEG-BCT-100
• Has received systemic cancer therapy, e.g. chemotherapy, targeted biologic or enzymes, either approved or investigational, ≤ 2 weeks prior to the first dose of PEG-BCT-100.
• Any toxic effects (except hair loss) of the prior therapy have not been resolved to Grade 2 or less according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events.
• Prior malignancy except cervical carcinoma in situ or treated basal cell carcinoma. Any cancers treated curatively > 5 years prior to study entry are permitted.
• Child-Pugh class of B or C
• Patients with ascites uncontrolled by medication
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
• Prior treatment with arginine depleting agent.
• Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment. The definition of effective contraception should be in agreement with local regulation and based on the judgment of the principal investigator or a designated associate.
• A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
• Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
• Subjects, who in the opinion of the Investigator, are unable to comply with the trial treatment and the related trial procedures.