A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.

Abstract

BACKGROUND:

Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients.

METHODS:

Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design.

RESULTS:

Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients.

CONCLUSION:

Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.

• Authors: Thomas Yau, P N Cheng, Pierre Chan, William Chan, Li Chen, Jimmy Yuen, Roberta Pang, S T Fan, Ronnie T Poon
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 1 Pg. 99-107 (Feb 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 22426640 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• Polyethylene Glycols
• Arginine
• Arginase

Topics

• Adult
• Aged
• Arginase (administration & dosage, chemistry, pharmacokinetics)
• Arginine (blood)
• Carcinoma, Hepatocellular (blood, drug therapy, pathology)
• Female
• Humans
• Liver Neoplasms (blood, drug therapy, pathology)
• Male
• Middle Aged
• Polyethylene Glycols
• Recombinant Proteins (administration & dosage, chemistry, pharmacokinetics)