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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
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TitleA phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma
 
AuthorsYau, T1
Cheng, PN2
Chan, P3
Chan, W1
Chen, L2
Yuen, J4
Pang, R1
Fan, ST1
Poon, RT1
 
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
 
CitationInvestigational New Drugs, 2012 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s10637-012-9807-9
 
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.
 
DescriptionEpub ahead of print; Springer open access article
 
ISSN0167-6997
2012 Impact Factor: 3.498
2012 SCImago Journal Rankings: 0.907
 
DOIhttp://dx.doi.org/10.1007/s10637-012-9807-9
 
DC FieldValue
dc.contributor.authorYau, T
 
dc.contributor.authorCheng, PN
 
dc.contributor.authorChan, P
 
dc.contributor.authorChan, W
 
dc.contributor.authorChen, L
 
dc.contributor.authorYuen, J
 
dc.contributor.authorPang, R
 
dc.contributor.authorFan, ST
 
dc.contributor.authorPoon, RT
 
dc.date.accessioned2012-08-16T05:59:31Z
 
dc.date.available2012-08-16T05:59:31Z
 
dc.date.issued2012
 
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.description.naturepublished_or_final_version
 
dc.descriptionEpub ahead of print; Springer open access article
 
dc.identifier.citationInvestigational New Drugs, 2012 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s10637-012-9807-9
 
dc.identifier.citeulike10486414
 
dc.identifier.doihttp://dx.doi.org/10.1007/s10637-012-9807-9
 
dc.identifier.hkuros202713
 
dc.identifier.issn0167-6997
2012 Impact Factor: 3.498
2012 SCImago Journal Rankings: 0.907
 
dc.identifier.pmid22426640
 
dc.identifier.scopuseid_2-s2.0-84873814665
 
dc.identifier.urihttp://hdl.handle.net/10722/159918
 
dc.languageeng
 
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.publisher.placeUnited States
 
dc.relation.ispartofInvestigational New Drugs
 
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 carcinoma
 
dc.typeArticle
 
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<item><contributor.author>Yau, T</contributor.author>
<contributor.author>Cheng, PN</contributor.author>
<contributor.author>Chan, P</contributor.author>
<contributor.author>Chan, W</contributor.author>
<contributor.author>Chen, L</contributor.author>
<contributor.author>Yuen, J</contributor.author>
<contributor.author>Pang, R</contributor.author>
<contributor.author>Fan, ST</contributor.author>
<contributor.author>Poon, RT</contributor.author>
<date.accessioned>2012-08-16T05:59:31Z</date.accessioned>
<date.available>2012-08-16T05:59:31Z</date.available>
<date.issued>2012</date.issued>
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<identifier.uri>http://hdl.handle.net/10722/159918</identifier.uri>
<description>Epub ahead of print; Springer open access article</description>
<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 &gt;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.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. Bio-Cancer Treatment International Limited
  3. Ruttonjee Hospital Hong Kong
  4. Hong Kong Sanatorium and Hospital