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Originally published as JCO Early Release 10.1200/JCO.2002.02.082 on June 17 2002

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Journal of Clinical Oncology, Vol 20, Issue 18 (September), 2002: 3772-3784
© 2002 American Society for Clinical Oncology

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

By Joseph P. Eder, Jr, Jeffrey G. Supko, Jeffrey W. Clark, Thomas A. Puchalski, Rocio Garcia-Carbonero, David P. Ryan, Lawrence N. Shulman, Joann Proper, Moira Kirvan, Barbara Rattner, Susan Connors, Mary T. Keogan, Milos J. Janicek, William E. Fogler, Lowell Schnipper, Nancy Kinchla, Carolyn Sidor, Eric Phillips, Judah Folkman, Donald W. Kufe

From the Division of Adult Oncology, Dana-Farber Cancer Institute; Divisions of Hematology/Oncology, Departments of Medicine, Brigham and Women’s Hospital, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center; Department of Surgery, Children’s Hospital; and Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA; and EntreMed, Rockville, MD.

Address reprint requests to J.P. Eder, Jr, MD, Dana-Farber Cancer Institute, 44 Binney St, Rm M1B34, Boston, MA 02115; email: jeder{at}partners.org

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.

Preliminary results of the study were presented at the eleventh National Cancer Institute/European Organization for Research and Treatment of Cancer/American Association of Cancer Research symposium on new drugs in cancer therapy, Amsterdam, the Netherlands, November 7-10, 2000, and the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

The first two authors contributed equally to this study.

This article was published ahead of print at www.jco.org.


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