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

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO

PubMedID: 23104721

Seiwert TY, Darga T, Haraf D, Blair EA, Stenson K, Cohen EE, Salama JK, Villaflor V, Witt ME, Lingen MW, Weichselbaum RR, Vokes EE. A phase I dose escalation study of Ad GV.EGR.TNF.11D (TNFerade™ Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation. Ann Oncol. 2013;24(3):769-76.
BACKGROUND
AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-a) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-a 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 TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC).

METHODS
TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) 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 × 10(11) 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-a, and TNF-a receptors. Adenoviral DNA was detected in three biopsies from one patient.

CONCLUSIONS
TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.