title: Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Thomas
authors.initials: T
authors.lastname: Yau
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Pierre
authors.initials: P
authors.lastname: Chan
authors.forename: C Martin
authors.initials: CM
authors.lastname: Curtis
authors.forename: Philip S
authors.initials: PS
authors.lastname: Murphy
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gauvin
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hodge
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Dar
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000509:alpha-Fetoproteins; C516667:pazopanib