Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.

Abstract

This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

• Authors: Thomas Yau, Paul N Cheng, Pierre Chan, Li Chen, Jimmy Yuen, Roberta Pang, Sheung Tat Fan, Denys N Wheatley, Ronnie T Poon
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 2 Pg. 496-504 (Apr 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25666409 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Recombinant Proteins
• Polyethylene Glycols
• ARG1 protein, human
• Arginase

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Area Under Curve
• Arginase (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Carcinoma, Hepatocellular (drug therapy)
• Chemistry, Pharmaceutical
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Liver Neoplasms (drug therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Polyethylene Glycols (chemistry)
• Prospective Studies
• Quality of Life
• Recombinant Proteins
• Response Evaluation Criteria in Solid Tumors