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.