title: A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Departments of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA. James.Posey@cc.uab.edu
authors.forename: James A
authors.initials: JA
authors.lastname: Posey
authors.forename: Mohammad B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bookman
authors.forename: Anahit
authors.initials: A
authors.lastname: Nowrouzi
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thornton
authors.forename: Delicia E
authors.initials: DE
authors.lastname: Carey
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Lorenz
authors.forename: Amy P
authors.initials: AP
authors.lastname: Sing
authors.forename: Clay B
authors.initials: CB
authors.lastname: Siegall
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Mansoor N
authors.initials: MN
authors.lastname: Saleh
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D015331:Cohort Studies; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007983:Lewis Blood Group Antigens / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C089583:BR96 sFv-PE40; D000922:Immunotoxins; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011993:Recombinant Fusion Proteins