Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily
| Autor: | Jeffrey G. Supko, Jeffrey W. Clark, Moira Kirvan, Susan L. Connors, Thomas A. Puchalski, Barbara Rattner, Joann Proper, Rocio Garcia-Carbonero, C. Sidor, Joseph Paul Eder, Lowell E. Schnipper, Milos J. Janicek, William E. Fogler, David P. Ryan, Judah Folkman, Eric N. Phillips, Mary T. Keogan, Donald Kufe, Lawrence N. Shulman, Nancy M. Kinchla |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Male Vascular Endothelial Growth Factor A Cancer Research medicine.medical_specialty Time Factors medicine.medical_treatment Urinary system Basic fibroblast growth factor Phases of clinical research Angiogenesis Inhibitors Endothelial Growth Factors Gastroenterology chemistry.chemical_compound Pharmacokinetics Internal medicine Neoplasms medicine Humans Tissue Distribution Infusions Intravenous Aged Chemotherapy Lymphokines business.industry Vascular Endothelial Growth Factors Middle Aged Magnetic Resonance Imaging Peptide Fragments Recombinant Proteins Surgery Endostatins Vascular endothelial growth factor Oncology chemistry Creatinine Toxicity Female Fibroblast Growth Factor 2 Collagen Endostatin business |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 20(18) |
| ISSN: | 0732-183X |
| Popis: | PURPOSE: 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. PATIENTS AND METHODS: The daily dose was increased from 15 to 240 mg/m2 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/m2/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. CONCLUSION: rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m2 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. |
| Databáze: | OpenAIRE |
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