A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.

Academic Article

Abstract

  • 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/m(2), 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/m(2) with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m(2) 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 > or =0.384 mg/m(2). 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/m(2) 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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    Keywords

  • Adult, Aged, Antibodies, Monoclonal, Cohort Studies, Female, Humans, Immunotoxins, Lewis Blood-Group System, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms, Recombinant Fusion Proteins, Treatment Outcome
  • Author List

  • Posey JA; Khazaeli MB; Bookman MA; Nowrouzi A; Grizzle WE; Thornton J; Carey DE; Lorenz JM; Sing AP; Siegall CB
  • Start Page

  • 3092
  • End Page

  • 3099
  • Volume

  • 8
  • Issue

  • 10