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A Phase I Trial of the Single-Chain Immunotoxin SGN-10 (BR96 sFv-PE40) in Patients with Advanced Solid Tumors¹

Departments of Medicine [J. A. P., M. B. K., A. N., J. T., D. E. C., A. F. L., M. N. S.] and Pathology [W. E. G.], Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300; Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19046 [M. A. B.]; and Seattle Genetics, Inc., Bothell, Washington 98021 [J. M. L., A. P. S., C. B. S.]

Purpose: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (V_H) and variable light (V_L) regions of BR96 monoclonal antibody. This antibody is specific for a Lewis^Y (Le^Y)-related carbohydrate antigen expressed on multiple carcinomas.

Experimental Design: A total of 46 patients with Le^Y-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m², administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined.

Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m² with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m² dose revealed a t_[1/2] of 2.5 ± 0.3 h and a C_max of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of 0.384 mg/m². No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease.

Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m² with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.

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