title: Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors.
abstract: OBJECTIVE
  Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors.
  
  
  METHODS
  Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m2 was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m2. Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography.
  
  
  RESULTS
  Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen.
  
  
  CONCLUSIONS
  Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.
authors.affiliation: Department of Medicine, Section of Medical Oncology and University of Wisconsin Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, 53792, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Thomas
authors.forename: Rhoda Z
authors.initials: RZ
authors.lastname: Arzoomanian
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Fred
authors.initials: F
authors.lastname: Lee
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
authors.forename: Kendra
authors.initials: K
authors.lastname: Tutsch
authors.forename: Amy
authors.initials: A
authors.lastname: Dresen
authors.forename: Peter
authors.initials: P
authors.lastname: Geiger
authors.forename: James
authors.initials: J
authors.lastname: Pluda
authors.forename: William
authors.initials: W
authors.lastname: Fogler
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D015153:Blotting, Western; D003094:Collagen / Q000493:pharmacokinetics* / Q000494:pharmacology; D003952:Diagnostic Imaging; D004305:Dose-Response Relationship, Drug; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000097:blood; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008222:Lymphokines / Q000097:blood; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000378:metabolism*; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000494:pharmacology; D011994:Recombinant Proteins; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010446:Peptide Fragments; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003094:Collagen