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

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. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.