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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 1 1
Cheng, PN2
Chan, P3
Chan, W1
Chen, L2
Yuen, J4
Pang, R1 1
Fan, ST1 1 1
Poon, RT1 1 1
 
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.issn>0167-6997</identifier.issn>
<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