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

TitleA phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma
Authors
Issue Date2012
PublisherSpringer 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?
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.
DescriptionEpub ahead of print; Springer open access article
Persistent Identifierhttp://hdl.handle.net/10722/159918
ISSN
2013 Impact Factor: 2.927
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYau, Ten_US
dc.contributor.authorCheng, PNen_US
dc.contributor.authorChan, Pen_US
dc.contributor.authorChan, Wen_US
dc.contributor.authorChen, Len_US
dc.contributor.authorYuen, Jen_US
dc.contributor.authorPang, Ren_US
dc.contributor.authorFan, STen_US
dc.contributor.authorPoon, RTen_US
dc.date.accessioned2012-08-16T05:59:31Z-
dc.date.available2012-08-16T05:59:31Z-
dc.date.issued2012en_US
dc.identifier.citationInvestigational New Drugs, 2012en_US
dc.identifier.issn0167-6997-
dc.identifier.urihttp://hdl.handle.net/10722/159918-
dc.descriptionEpub ahead of print; Springer open access article-
dc.description.abstractBackground 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.languageengen_US
dc.publisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997-
dc.relation.ispartofInvestigational New Drugsen_US
dc.rightsThe original publication is available at www.springerlink.com-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleA phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinomaen_US
dc.typeArticleen_US
dc.identifier.emailYau, T: tyaucc@hku.hken_US
dc.identifier.emailChan, W: ylwchan@hku.hken_US
dc.identifier.emailPang, R: robertap@hku.hken_US
dc.identifier.emailFan, ST: stfan@hku.hken_US
dc.identifier.emailPoon, RT: poontp@hku.hken_US
dc.identifier.authorityYau, TCC=rp01466en_US
dc.identifier.authorityPang, RWC=rp00274en_US
dc.identifier.authorityFan, ST=rp00355en_US
dc.identifier.authorityPoon, RTP=rp00446en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1007/s10637-012-9807-9-
dc.identifier.pmid22426640-
dc.identifier.scopuseid_2-s2.0-84873814665-
dc.identifier.hkuros202713en_US
dc.identifier.isiWOS:000314029900012-
dc.publisher.placeUnited States-
dc.identifier.citeulike10486414-

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