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[Proceedings of the 11th NCI EORTC AACR Symposium]
Copyright 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy Published by the AACR.

258 Recombinant human endostatin demonstrates safety, linear pharmacokinetics and biological effects on tumor growth factors: Results of a phase I clinical study.

JP Eder, JW Clark, JG Supko, LN Shulman, R Garcia-Carbonero, K Roper, J Proper, M Keogan, LSchnipper, S Connors, C Butterfield, W Fogler, G Xu, E Gubish, J Folkman, and DW Kufe. Dana-Farber/Harvard Cancer Center Boston MA and EntreMed, Rockville MD.

rhEndostatin is a 20 kilodalton protein derived from Collagen XVIII with potent antiangiogenic activity. A phase I trial investigating an initial daily 20 min infusion in adults with refractory solid tumors was performed to determine the safety, pharmacokinetics (PK) and biological activity of rhEndostatin. Patients (3/cohort) without dose limiting toxicity and with < 50% progression of tumor receive additional rhEndostatin at dose levels of 15, 30, 60, 120, and 240 mg/m2. The only toxicity was a transient grade I rash seen in 2 patients. Serum levels of rhEndostatin were monitored using a polyclonal ELISA assay. rhEndostatin exhibited linear PK at all dose levels evaluated based on parameters estimated from the day 1 serum profile. There was no drug accumulation or evidence of altered PK based on monitoring peak serum levels during 2 courses of therapy.

the 240 mg/m2 dose, the peak rhEndostatin serum level was 11 ug/mL and the mean area under the curve(AUC) was approximately 700 ug*min/ml. This was similar to the AUC for a 50 mg/kg dose in mice, which was shown to be efficacious in tumor xenograft models. Antibodies to rhEndostatin were detected in 5 patients but had no apparent effect on PK. Assays of endothelial proliferation showed inhibition by patient serum obtained after rhEndostatin treatment. Urine levels of bFGF and VEGF, normalized to creatinine, showed a dose dependent decrease from baseline values in 8 of 9 patients at doses 60 mg/m2. Stable disease was demonstrated in several patients at all dose levels and 1 patient showed radiographic regression (<50%) of advanced metastatic pancreatic neuroendocrine cancer while receiving rhEndostatin. To further define pharmacokinetics and pharmacodynamics, additional patients will be enrolled at the 60 and 240 mg/m2 dose levels.

Published as a Supplement to Clinical Cancer Research
Volume 6, November 2000
ISSN 1078-0432

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