PMID- 22426640
OWN - NLM
STAT- MEDLINE
DCOM- 20130731
LR  - 20211021
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 31
IP  - 1
DP  - 2013 Feb
TI  - A phase 1 dose-escalating study of pegylated recombinant human arginase 1 
      (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.
PG  - 99-107
LID - 10.1007/s10637-012-9807-9 [doi]
AB  - 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.
FAU - Yau, Thomas
AU  - Yau T
AD  - Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 
      Pokfulam, Hong Kong, China.
FAU - Cheng, P N
AU  - Cheng PN
FAU - Chan, Pierre
AU  - Chan P
FAU - Chan, William
AU  - Chan W
FAU - Chen, Li
AU  - Chen L
FAU - Yuen, Jimmy
AU  - Yuen J
FAU - Pang, Roberta
AU  - Pang R
FAU - Fan, S T
AU  - Fan ST
FAU - Poon, Ronnie T
AU  - Poon RT
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120317
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Recombinant Proteins)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Arginase/*administration & dosage/chemistry/pharmacokinetics
MH  - Arginine/blood
MH  - Carcinoma, Hepatocellular/blood/*drug therapy/pathology
MH  - Female
MH  - Humans
MH  - Liver Neoplasms/blood/*drug therapy/pathology
MH  - Male
MH  - Middle Aged
MH  - Polyethylene Glycols
MH  - Recombinant Proteins/*administration & dosage/chemistry/pharmacokinetics
PMC - PMC3553413
EDAT- 2012/03/20 06:00
MHDA- 2013/08/01 06:00
PMCR- 2012/03/17
CRDT- 2012/03/20 06:00
PHST- 2012/01/05 00:00 [received]
PHST- 2012/02/22 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2013/08/01 06:00 [medline]
PHST- 2012/03/17 00:00 [pmc-release]
AID - 9807 [pii]
AID - 10.1007/s10637-012-9807-9 [doi]
PST - ppublish
SO  - Invest New Drugs. 2013 Feb;31(1):99-107. doi: 10.1007/s10637-012-9807-9. Epub 
      2012 Mar 17.