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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.

259 A phase I clinical trial of recombinant human endostatin (rHE) in patients (PTS) with solid tumors: Pharmacokinetic (PK), safety and efficacy analysis.

R. Herbst, H.Tran, K. Hess, T. Madden, C. Charnsangavej, D. Gravel, K. Terry, M. Guerra, K. Taebel, L. Ellis, J. Pluda, W.K. Hong, J. Abbruzzese. UT M. D. Anderson Cancer Center, Houston, Texas and CTEP, NCI, NIH.

Endostatin has antiangiogenic and apoptotic activity against endothelial cells in culture and induces tumor regression in preclinical models. rHE has been administered in escalating doses to pts with solid tumors. The primary endpoint was to determine a biologically effective dose (BED) by measuring microvascular density and endothelial cell apoptosis in tumor tissue. Safety, hRE PK, and non-invasive radiologic evaluations of tumor vascularity were also studied. Fifteen patients (9M/6F; median age 54 yrs.) have been treated using a daily 20 min iv infusion. Cycles were defined by 28-day periods, and in the absence of symptoms or dose limiting toxicity patients were allowed to continue rHE with 100% progression in measurable disease. Three PTS per level have been treated (see Table). Tumor diagnoses: melanoma (3), NSCLC (2), colon (2), sarcoma (3), breast (2), kidney (2), H/N (1). To date, 40 cycles of rHE have been administered without any grade 3 or 4 toxic effects. PK analysis was performed in 14 patients. Baseline rHE-related protein concentrations in these subjects ranged from 12-31 ng/ml.

Dose Level (mg/m2)
No. of Patients
Mean Cl (ml/min/m2)
Mean Est. Cmax (g/ml)
Mean AUC (ug/ml*min)
369 200
0.30 0.01
50 26.3
383 38
0.36 0.16
78.8 7.4
231 139
0.94 0.19
150.2 7.9
516 143
2.6 0.15
243.4 59
369 8.8
5.0 0.7
487.7 12.2

A linear 2-compartment model best described the PK data. We estimate that the target Cmax and AUC associated with rHE preclinical activity will be reached at our next dose level of 300 mg/m2. Using traditional response criteria, the median time to PD (from start of treatment) was 45 days (95% CI 26-82 days). Additional study will be necessary to determine BED and establish efficacy.

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

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