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
Mené sur 14 patients atteints d'un cancer récidivant de la tête et du cou déjà traité par radiothérapie, cet essai de phase I évalue la dose maximale tolérée et la dose limite de toxicité d'un vecteur adénoviral exprimant TNF-α en combinaison avec une chimioradiothérapie concomitante
Background AdGV.EGR.TNF.11D (TNFerade™ 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 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 × 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 TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 1010 PU. Monitoring for thrombotic events is indicated.
Annals of Oncology 2012