Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer

Lee H. Pai, Michael A. Bookman, Robert F. Ozols, Robert C. Young, John W. Smith, Dan L. Longo, Bruce Gould, Arthur Frankel, Edward F. McClay, Stephen Howell, Eddie Reed, Mark C. Willingham, David J. FitzGerald, Ira Pastan

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 μg/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 μg/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 μg/kg doses, levels remained high for up to 24 hours (> 100 ng/mL) and then gradually decreased and became undetectable (< 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 μg/kg and 2 μg/kg, serum levels were not detectable (< 5 ng/mL). However, after doses of 5 or 10 μg/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 μg/kg (x 3) and 10 μg/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.

Original languageEnglish (US)
Pages (from-to)2095-2103
Number of pages9
JournalJournal of Clinical Oncology
Volume9
Issue number12
DOIs
StatePublished - Jan 1 1991

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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