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Article: Phase I dose-finding study of pazopanib in hepatocellular carcinoma: Evaluation of early efficacy, pharmacokinetics, and pharmacodynamics

TitlePhase I dose-finding study of pazopanib in hepatocellular carcinoma: Evaluation of early efficacy, pharmacokinetics, and pharmacodynamics
Authors
KeywordsPazopanib
Abdominal distension
Abdominal pain
Advanced cancer
Alanine aminotransferase blood level
Issue Date2011
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2011, v. 17 n. 21, p. 6914-6923 How to Cite?
AbstractBackground: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C max and area under the concentration-time curve (AUC 0-6) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K trans were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C 24 and C max values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/142546
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
Funding AgencyGrant Number
GlaxoSmithKline Research and Development
GlaxoSmithKline
Funding Information:

This study was sponsored by GlaxoSmithKline Research and Development and GlaxoSmithKline provided funding for medical editorial assistance and financial support for this study; medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Philadelphia, PA.

References

 

DC FieldValueLanguage
dc.contributor.authorYau, Ten_HK
dc.contributor.authorChen, PJen_HK
dc.contributor.authorChan, Pen_HK
dc.contributor.authorCurtis, CMen_HK
dc.contributor.authorMurphy, PSen_HK
dc.contributor.authorSuttle, ABen_HK
dc.contributor.authorGauvin, Jen_HK
dc.contributor.authorHodge, JPen_HK
dc.contributor.authorDar, MMen_HK
dc.contributor.authorPoon, RTen_HK
dc.date.accessioned2011-10-28T02:50:58Z-
dc.date.available2011-10-28T02:50:58Z-
dc.date.issued2011en_HK
dc.identifier.citationClinical Cancer Research, 2011, v. 17 n. 21, p. 6914-6923en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142546-
dc.description.abstractBackground: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C max and area under the concentration-time curve (AUC 0-6) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K trans were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C 24 and C max values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. ©2011 AACR.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research.en_US
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subjectPazopanib-
dc.subjectAbdominal distension-
dc.subjectAbdominal pain-
dc.subjectAdvanced cancer-
dc.subjectAlanine aminotransferase blood level-
dc.titlePhase I dose-finding study of pazopanib in hepatocellular carcinoma: Evaluation of early efficacy, pharmacokinetics, and pharmacodynamicsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=&spage=&epage=&date=2011&atitle=Phase+I+Dose-Finding+Study+of+Pazopanib+in+Hepatocellular+Carcinoma:+Evaluation+of+Early+Efficacy,+Pharmacokinetics,+and+Pharmacodynamicsen_US
dc.identifier.emailYau, T: tyaucc@hku.hken_HK
dc.identifier.emailPoon, RT: poontp@hkucc.hku.hken_HK
dc.identifier.authorityYau, T=rp01466en_HK
dc.identifier.authorityPoon, RT=rp00446en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-11-0793en_HK
dc.identifier.pmid21831954-
dc.identifier.scopuseid_2-s2.0-80455132308en_HK
dc.identifier.hkuros196698en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80455132308&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume17en_HK
dc.identifier.issue21en_HK
dc.identifier.spage6914en_HK
dc.identifier.epage6923en_HK
dc.identifier.eissn1557-3265-
dc.identifier.isiWOS:000296624000035-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYau, T=23391533100en_HK
dc.identifier.scopusauthoridChen, PJ=7408354514en_HK
dc.identifier.scopusauthoridChan, P=7403497841en_HK
dc.identifier.scopusauthoridCurtis, CM=54416972300en_HK
dc.identifier.scopusauthoridMurphy, PS=7401685759en_HK
dc.identifier.scopusauthoridSuttle, AB=6603648361en_HK
dc.identifier.scopusauthoridGauvin, J=25652758500en_HK
dc.identifier.scopusauthoridHodge, JP=7103254962en_HK
dc.identifier.scopusauthoridDar, MM=15756814700en_HK
dc.identifier.scopusauthoridPoon, RT=7103097223en_HK

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