A Multicenter Phase I Gene Therapy Clinical Trial Involving Intraperitoneal Administration of E1A-Lipid Complex in Patients with Recurrent Epithelial Ovarian Cancer Overexpressing HER-2/neu Oncogene

Srinivasan Madhusudan, Ayala Tamir, Nicholas Bates, Elizabeth Flanagan, Martin E. Gore, Desmond P.J. Barton, Peter Harper, Michael Seckl, Hilary Thomas, Nicholas R. Lemoine, Mark Charnock, Nagy A. Habib, Robert Lechler, Joanna Nicholls, Massimo Pignatelli, Trivadi S. Ganesan

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Abstract

Purpose: HER-2/neu oncogene is overexpressed in 10-30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients. Experimental Design: A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m 2, given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity Results: Fifteen patients, with a median age of 57 years (range, 43-81) were recruited. Three (1.8 mg DNA/m2), 4 (3.6 mg DNA/m2), and 8 patients (7.2 mg DNA/m2) received i.p. E1A. A total of 91 infusions (range, 1-18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m2. E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity. Conclusions: I.P. E1A-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.

Original languageEnglish
Pages (from-to)2986-2996
Number of pages11
JournalClinical Cancer Research
Volume10
Issue number9
DOIs
Publication statusPublished - May 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Madhusudan, S., Tamir, A., Bates, N., Flanagan, E., Gore, M. E., Barton, D. P. J., Harper, P., Seckl, M., Thomas, H., Lemoine, N. R., Charnock, M., Habib, N. A., Lechler, R., Nicholls, J., Pignatelli, M., & Ganesan, T. S. (2004). A Multicenter Phase I Gene Therapy Clinical Trial Involving Intraperitoneal Administration of E1A-Lipid Complex in Patients with Recurrent Epithelial Ovarian Cancer Overexpressing HER-2/neu Oncogene. Clinical Cancer Research, 10(9), 2986-2996. https://doi.org/10.1158/1078-0432.CCR-03-0291