title: 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.
  
  
  CONCLUSIONS
  Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
authors.forename: Thomas
authors.initials: T
authors.lastname: Yau
authors.forename: P N
authors.initials: PN
authors.lastname: Cheng
authors.forename: Pierre
authors.initials: P
authors.lastname: Chan
authors.forename: William
authors.initials: W
authors.lastname: Chan
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Jimmy
authors.initials: J
authors.lastname: Yuen
authors.forename: Roberta
authors.initials: R
authors.lastname: Pang
authors.forename: S T
authors.initials: ST
authors.lastname: Fan
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
mesh_terms: D000328:Adult; D000368:Aged; D001119:Arginase / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001120:Arginine / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D001120:Arginine; D001119:Arginase