A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients.
BACKGROUND
Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.


METHODS
Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m(-2). The primary end point was disease-control rate (DCR).


RESULTS
Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5-43.1) and 7.3 (95% CI: 4.7-9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1-17.9) and 5.8 (95% CI: 1.4-10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1-2 local and/or allergic reactions.


CONCLUSIONS
ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.
Yang
T-S
TS
Department of Internal Medicine, Chang Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taoyuan 33305, Taiwan.
Lu
S-N
SN
Chao
Y
Y
Sheen
I-S
IS
Lin
C-C
CC
Wang
T-E
TE
Chen
S-C
SC
Wang
J-H
JH
Liao
L-Y
LY
Thomson
J A
JA
Wang-Peng
J
J
Chen
P-J
PJ
Chen
L-T
LT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001120:Arginine / Q000097:blood; D044466:Asian People; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D019233:Retreatment
D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20
Autophagy. 2009 May;5(4):567-8
19276647
Immunobiology. 2007;212(9-10):795-812
18086380
Curr Oncol Rep. 2008 May;10(3):199-205
18765149
J Clin Gastroenterol. 2002 Nov-Dec;35(5 Suppl 2):S109-14
12394214
Biomed Pharmacother. 2002 Nov;56(9):439-45
12481980
Am J Epidemiol. 2003 Apr 15;157(8):674-82
12697571
Oncologist. 2007 Dec;12(12):1425-32
18165619
J Clin Oncol. 2010 May 1;28(13):2220-6
20351325
Cancer. 2008 Jan 15;112(2):250-9
18041064
J Clin Oncol. 2004 May 15;22(10):1815-22
15143074
Hepatogastroenterology. 2003 Sep-Oct;50(53):1214-6
14571701
J Gastroenterol Hepatol. 2006 Oct;21(10):1561-6
16928217
Exp Cell Res. 1960 Jun;20:84-91
13840125
Int J Cancer. 2010 Jun 15;126(12):2762-72
20104527
N Engl J Med. 2008 Jul 24;359(4):378-90
18650514
Liver. 1986 Jun;6(3):133-7
2427909
Cancer. 2004 Feb 15;100(4):826-33
14770441
J Infect Dis. 1963 Jan-Feb;112:7-16
14031982
Lancet Oncol. 2009 Jan;10(1):25-34
19095497
Int J Cancer. 1992 May 8;51(2):244-9
1568792
J Clin Oncol. 2009 Dec 20;27(36):e271; author reply e272
19917866
J Control Release. 2002 Apr 23;80(1-3):259-71
11943403
Rev Gastroenterol Disord. 2003 Winter;3(1):8-24
12684589
Nat Rev Immunol. 2005 Aug;5(8):641-54
16056256
Control Clin Trials. 1989 Mar;10(1):1-10
2702835
Jpn J Cancer Res. 1993 Nov;84(11):1195-200
8276724
Gut. 2003 May;52 Suppl 3:iii1-8
12692148
Int J Cancer. 2003 Sep 20;106(5):723-8
12866032
Cancer Lett. 2006 Jan 8;231(1):30-5
16356828
Proc Soc Exp Biol Med. 1964 Dec;117:910-8
14244988
Proc Soc Exp Biol Med. 1963 Feb;112:381-7
14035371
Clin Cancer Res. 1999 Oct;5(10):2726-34
10537335
Cancer Res. 1990 Jan 15;50(2):345-9
2403840
J Gastroenterol. 2005 Mar;40(3):225-35
15830281
Int J Cancer. 2008 Oct 15;123(8):1950-5
18661517
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
Cancer Res. 2002 Oct 1;62(19):5443-50
12359751
Gastroenterology. 2007 Jun;132(7):2557-76
17570226