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

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Publisher Website: 10.1007/s10637-012-9807-9
Scopus: eid_2-s2.0-84873814665
PMID: 22426640

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Title	A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma
Authors	Yau, T1 1 1 Cheng, PN2 Chan, P3 Chan, W1 Chen, L2 Yuen, J4 Pang, R1 1 Fan, ST1 1 1 Poon, RT1 1 1
Issue Date	2012
Publisher	Springer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997
Citation	Investigational New Drugs, 2012 [How to Cite?] DOI: http://dx.doi.org/10.1007/s10637-012-9807-9
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.
Description	Epub ahead of print; Springer open access article
ISSN	0167-6997 2011 Impact Factor: 3.357 2011 SCImago Journal Rankings: 0.223
DOI	http://dx.doi.org/10.1007/s10637-012-9807-9

DC Field	Value
dc.contributor.author	Yau, T
dc.contributor.author	Cheng, PN
dc.contributor.author	Chan, P
dc.contributor.author	Chan, W
dc.contributor.author	Chen, L
dc.contributor.author	Yuen, J
dc.contributor.author	Pang, R
dc.contributor.author	Fan, ST
dc.contributor.author	Poon, RT
dc.date.accessioned	2012-08-16T05:59:31Z
dc.date.available	2012-08-16T05:59:31Z
dc.date.issued	2012
dc.description.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.
dc.description.nature	published_or_final_version
dc.description	Epub ahead of print; Springer open access article
dc.identifier.citation	Investigational New Drugs, 2012 [How to Cite?] DOI: http://dx.doi.org/10.1007/s10637-012-9807-9
dc.identifier.citeulike	10486414
dc.identifier.doi	http://dx.doi.org/10.1007/s10637-012-9807-9
dc.identifier.hkuros	202713
dc.identifier.issn	0167-6997 2011 Impact Factor: 3.357 2011 SCImago Journal Rankings: 0.223
dc.identifier.pmid	22426640
dc.identifier.scopus	eid_2-s2.0-84873814665
dc.identifier.uri	http://hdl.handle.net/10722/159918
dc.language	eng
dc.publisher	Springer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997
dc.publisher.place	United States
dc.relation.ispartof	Investigational New Drugs
dc.rights	The original publication is available at www.springerlink.com
dc.rights	Creative Commons: Attribution 3.0 Hong Kong License
dc.title	A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma
dc.type	Article

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Author Affiliations

The University of Hong Kong
Bio-Cancer Treatment International Limited
Ruttonjee Hospital Hong Kong
Hong Kong Sanatorium and Hospital