Phase I S tudy o f R ecombinant H uman E ndostatin i n Patients W ith A dvanced S olid T umors

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/m 2 /d, and seven patients were treated at 300 mg/m 2 /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 rhEndo. 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/m 2 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. J Clin Oncol 20:3792-3803. © 2002 by American Society of Clinical Oncology.