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

Tanguy Lim 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

Research output: Contribution to journalArticle

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 1 2013
Externally publishedYes

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Chemoradiotherapy
Head and Neck Neoplasms
Tumor Necrosis Factor-alpha
Maximum Tolerated Dose
Biopsy
Radiation-Sensitizing Agents
Hydroxyurea
Tumor Necrosis Factor Receptors
Fluorouracil
Neoplasms
Re-Irradiation
Radiation
Survival
DNA
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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

In: Annals of Oncology, Vol. 24, No. 3, mds523, 01.03.2013, p. 769-776.

Research output: Contribution to journalArticle

Lim Seiwert, T, Darg, T, Haraf, D, Blair, EA, Stenson, K, Cohen, EEW, Salama, JK, Villaflor, V, Witt, ME, Lingen, MW, Weichselbaum, RR & Vokes, EE 2013, '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', Annals of Oncology, vol. 24, no. 3, mds523, pp. 769-776. https://doi.org/10.1093/annonc/mds523
Lim Seiwert, Tanguy ; Darg, T. ; Haraf, D. ; Blair, E. A. ; Stenson, K. ; Cohen, E. E.W. ; Salama, J. K. ; Villaflor, V. ; Witt, M. E. ; Lingen, M. W. ; Weichselbaum, R. R. ; Vokes, E. E. / 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. In: Annals of Oncology. 2013 ; Vol. 24, No. 3. pp. 769-776.
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title = "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.",
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T1 - 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

AU - Lim Seiwert, Tanguy

AU - Darg, T.

AU - Haraf, D.

AU - Blair, E. A.

AU - Stenson, K.

AU - Cohen, E. E.W.

AU - Salama, J. K.

AU - Villaflor, V.

AU - Witt, M. E.

AU - Lingen, M. W.

AU - Weichselbaum, R. R.

AU - Vokes, E. E.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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.

AB - 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.

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KW - Recurrent disease

KW - Translational research

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