A phase I dose escalation study of ad GV.EGR.TNF.11D (TNFeradeTMM Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation

T. Y. Seiwert*, T. Darg, D. Haraf, E. A. Blair, K. Stenson, E. E W Cohen, J. K. Salama, V. Villaflor, M. E. Witt, M. W. Lingen, R. R. Weichselbaum, E. E. Vokes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: AdGV.EGR.TNF.11D (TNFeradeTMM Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFeradeTMM Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). Methods: TNFeradeTMM Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 109 to 4 × 1011 PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. Results: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 1011 PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. Conclusions: TNFeradeTMM Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 1010 PU. Monitoring for thrombotic events is indicated.

Original languageEnglish (US)
Article numbermds523
Pages (from-to)769-776
Number of pages8
JournalAnnals of Oncology
Volume24
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Chemoradiation
  • Gene therapy
  • Head and neck cancer
  • Recurrent disease
  • Translational research

ASJC Scopus subject areas

  • Hematology
  • Oncology

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