title: Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.
abstract: OBJECTIVE
  To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors.
  
  
  METHODS
  The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.
  
  
  RESULTS
  There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.
  
  
  CONCLUSIONS
  rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
authors.affiliation: Division of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. jelder@partners.org
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Shulman
authors.forename: Joann
authors.initials: J
authors.lastname: Proper
authors.forename: Moira
authors.initials: M
authors.lastname: Kirvan
authors.forename: Barbara
authors.initials: B
authors.lastname: Rattner
authors.forename: Susan
authors.initials: S
authors.lastname: Connors
authors.forename: Mary T
authors.initials: MT
authors.lastname: Keogan
authors.forename: Milos J
authors.initials: MJ
authors.lastname: Janicek
authors.forename: William E
authors.initials: WE
authors.lastname: Fogler
authors.forename: Lowell
authors.initials: L
authors.lastname: Schnipper
authors.forename: Nancy
authors.initials: N
authors.lastname: Kinchla
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sidor
authors.forename: Eric
authors.initials: E
authors.lastname: Phillips
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Kufe
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003094:Collagen / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000652:urine; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D008222:Lymphokines / Q000652:urine; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; 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; 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; D003404:Creatinine