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

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.

• Authors: James A Posey, Mohammad B Khazaeli, Michael A Bookman, Anahit Nowrouzi, William E Grizzle, Jennifer Thornton, Delicia E Carey, Jennifer M Lorenz, Amy P Sing, Clay B Siegall, Albert F LoBuglio, Mansoor N Saleh
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 10 Pg. 3092-9 (Oct 2002) ISSN: 1078-0432 [Print] United States
• PMID: 12374676 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• BR96 sFv-PE40
• Immunotoxins
• Lewis Blood Group Antigens
• Lewis Y antigen
• Recombinant Fusion Proteins

Topics

• Adult
• Aged
• Antibodies, Monoclonal
• Cohort Studies
• Female
• Humans
• Immunotoxins (adverse effects, pharmacokinetics, therapeutic use)
• Lewis Blood Group Antigens (immunology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (immunology, pathology, therapy)
• Recombinant Fusion Proteins (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome