Originally published as JCO Early Release 10.1200/JCO.2002.11.061 on July 29 2002
Journal of Clinical Oncology, Vol 20, Issue 18
(September), 2002: 3792-3803
© 2002 American Society for Clinical Oncology
Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors
By Roy S. Herbst,
Kenneth R. Hess,
Hai T. Tran,
Jennifer E. Tseng,
Nizar A. Mullani,
Chusilp Charnsangavej,
Timothy Madden,
Darren W. Davis,
David J. McConkey,
Michael S. O’Reilly,
Lee M. Ellis,
James Pluda,
Waun K. Hong,
James L. Abbruzzese
From the Departments of Thoracic and Head and Neck Medical Oncology, Biostatistics, Diagnostic Radiology, Pharmaceutical Sciences, Cancer Biology, Radiation Oncology, Surgical Oncology, and Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, and University of Texas Houston Health Science Center, Houston, TX, and National Cancer Institute, Bethesda, MD.
Address reprint requests to Roy S. Herbst, MD, PhD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030.
PURPOSE: Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors.
PATIENTS AND METHODS: Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m2/d, and seven patients were treated at 300 mg/m2/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers.
RESULTS: Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 ± 4.1 hours. A dose of 300 mg/m2 achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo’s activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed.
CONCLUSION: rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.
Presented in part at the Thirty-Seventy Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
This article was published ahead of print at www.jco.org.
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