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Phase II Study of Recombinant Human Endostatin in Patients With Advanced Neuroendocrine Tumors

Matthew H. Kulke, Emily K. Bergsland, David P. Ryan, Peter C. Enzinger, Thomas J. Lynch, Andrew X. Zhu, Jeffrey A. Meyerhardt, John V. Heymach, William E. Fogler, Carolyn Sidor, Ann Michelini, Kate Kinsella, Alan P. Venook, Charles S. Fuchs

From the Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School; Department of Hematology/Oncology, Massachusetts General Hospital; Channing Laboratory, Brigham and Women's Hospital, Boston, MA; University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA; and Entremed Inc, Rockville, MD

Address reprint requests to Matthew H. Kulke, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: matthew_kulke{at}dfci.harvard.edu

PURPOSE: Endostatin is a 20-kd proteolytic fragment of collagen XVIII that, in preclinical studies, has been shown to have antiangiogenic and antitumor activity. Both preclinical and human phase I studies of recombinant human endostatin (rhEndostatin) suggested activity in neuroendocrine tumors, which are known to be hypervascular. We therefore performed a multicenter phase II study of rhEndostatin in patients with carcinoid or pancreatic neuroendocrine tumors.

PATIENTS AND METHODS: Forty-two patients with advanced pancreatic endocrine tumors or carcinoid tumors were treated with rhEndostatin administered as a bid subcutaneous injection at a starting dose of 60 mg/m²/d. Steady-state trough levels were obtained after 6 weeks of therapy; patients who did not achieve a target therapeutic level of 300 ng/mL underwent dose escalation to 90 mg/m²/d. Patients were observed for evidence of toxicity, response, and survival.

RESULTS: rhEndostatin was associated with minimal toxicity. However, among 40 patients assessable for radiologic response, none experienced partial response to therapy, as defined by WHO criteria. The median steady-state trough level achieved after dose escalation was 331 ng/mL, within the postulated therapeutic range.

CONCLUSION: Treatment with rhEndostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors.

Supported by Entremed Inc. Supported in part by National Institutes of Health Grants No. K23 CA 093401 and K30 HL04095, and gifts from Raymond and Beverly Sackler, the Caring for Carcinoid Foundation, and the Stephen and Caroline Kaufer Fund for Neuroendocrine Tumor Research (M.H.K.).

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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