title: 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.
abstract: 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 × 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-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 × 10(10) PU. Monitoring for thrombotic events is indicated.
authors.affiliation: Departments of Medicine, The University of Chicago, Chicago, IL 60615, USA. tseiwert@medicine.bsd.uchicago.edu
authors.forename: T Y
authors.initials: TY
authors.lastname: Seiwert
authors.forename: T
authors.initials: T
authors.lastname: Darga
authors.forename: D
authors.initials: D
authors.lastname: Haraf
authors.forename: E A
authors.initials: EA
authors.lastname: Blair
authors.forename: K
authors.initials: K
authors.lastname: Stenson
authors.forename: E E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: J K
authors.initials: JK
authors.lastname: Salama
authors.forename: V
authors.initials: V
authors.lastname: Villaflor
authors.forename: M E
authors.initials: ME
authors.lastname: Witt
authors.forename: M W
authors.initials: MW
authors.lastname: Lingen
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000628:therapy*; D059248:Chemoradiotherapy; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D019583:Dose Fractionation, Radiation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000628:therapy*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011880:Radiotherapy Planning, Computer-Assisted; D050397:Radiotherapy, Intensity-Modulated; D019233:Retreatment; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D011838:Radiation-Sensitizing Agents; C572333:TNFeraseBiologic; D004247:DNA; D005472:Fluorouracil; D006918:Hydroxyurea