[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy Published by the AACR.
J260 A phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin.
J P Thomas, J Schiller, F. Lee, S. Perlman, A. Friedl, T. Winter, R. Marnocha, R. Arzoomanian, D. Alberti, K. Binger, J. Volkman, C. Feierabend, K. Tutsch, A. Dresen, R. Auerbach, J. Pluda, and G. Wilding. University of Wisconsin Comprehensive Cancer Center, Madison, WI.
Endostatin is a 20 kilodalton antiangiogenic protein derived from the C terminal portion of Collagen XVIII. We are conducting a phase I clinical study of recombinant human endostatin in patients with refractory solid tumors, using a 1 hour infusion given daily. Patients were allowed to remain on study in the absence of dose-limiting toxicities with up to 50% increase in measurable tumor. Dose levels included 30, 60, 100 and 150 mg/m2 with escalation to 225 and 300 mg/m2 planned. Tumor vasculature was assessed by dynamic CT evaluation, Doppler ultrasound and MRI. Endostatin effects on skin angiogenesis was evaluated by punch biopsies. Double staining techniques were employed for endothelial cell density, proliferation and apoptosis. Tumor biopsies were obtained from all patients and similarly analyzed. Antiangiogenic activity in patient serum was studied in a matrigel plug assay. Serum was also assayed for VEGF and bFGF. 15 patients, enrolled to date, have tolerated therapy very well. A single grade 1 allergic reaction was observed. Endostatin PK's utilized a polyclonal EIA assay (CytImmune). Serum endostatin levels pretreatment (25.9) were higher than in volunteers without cancer (17.4). Serum t1/2 was biexponential with an intial t1/2 of 45.2 minutes and a t1/2 = 21.6 hours. Clearance was not dose related (24.01 L/hr/m2). The day 1 AUC (corrected for preexisting endostatin levels) was 1.53, 2.4 and 4.9 µg/ml/hr at the 30, 60 and 100 mg/m2 dose levels respectively. The Cmax at these dose levels were 577.8, 1183 and 2466.7 ng/ml. Peak dose levels and AUCs were similar to those achieving antiangiogenic and antitumor effects in mice. Pharmacokinetics were linear at all doses (Cmax vs dose r2=0.852). Radiologic evidence for changes in microvessel density was demonstrated as were decreases in serum of VEGF levels after starting endostatin in some patients.
Volume 6, November 2000