Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2003 Jan 15;21(2):223-31
Date
01/15/2003Pubmed ID
12525513DOI
10.1200/JCO.2003.12.120Scopus ID
2-s2.0-0037440123 (requires institutional sign-in at Scopus site) 227 CitationsAbstract
PURPOSE: 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.
PATIENTS AND 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.
CONCLUSION: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.
Author List
Thomas JP, Arzoomanian RZ, Alberti D, Marnocha R, Lee F, Friedl A, Tutsch K, Dresen A, Geiger P, Pluda J, Fogler W, Schiller JH, Wilding GAuthor
James P. Thomas MD, PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Angiogenesis Inhibitors
Blotting, Western
Collagen
Diagnostic Imaging
Dose-Response Relationship, Drug
Endostatins
Endothelial Growth Factors
Female
Fibroblast Growth Factor 2
Humans
Infusions, Intravenous
Intercellular Signaling Peptides and Proteins
Lymphokines
Male
Middle Aged
Neoplasms
Neovascularization, Pathologic
Peptide Fragments
Recombinant Proteins
Tissue Distribution
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
