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

T. Y. 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

doi:10.1093/annonc/mds523

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

T. Y. 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 journal › Article › peer-review

16 Scopus citations

Abstract

Background: AdGV.EGR.TNF.11D (TNFerade^TMM 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^TMM Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). Methods: TNFerade^TMM 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^TMM Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 1010 PU. Monitoring for thrombotic events is indicated.

Original language	English (US)
Article number	mds523
Pages (from-to)	769-776
Number of pages	8
Journal	Annals of Oncology
Volume	24
Issue number	3
DOIs	https://doi.org/10.1093/annonc/mds523
State	Published - Mar 2013
Externally published	Yes

Keywords

Chemoradiation
Gene therapy
Head and neck cancer
Recurrent disease
Translational research

ASJC Scopus subject areas

Hematology
Oncology

Access to Document

10.1093/annonc/mds523

Cite this

Seiwert, T. Y., 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. (2013). A phase I dose escalation study of ad GV.EGR.TNF.11D (TNFerade^TMM Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation. Annals of Oncology, 24(3), 769-776. Article mds523. https://doi.org/10.1093/annonc/mds523

Seiwert, TY, 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 (TNFerade^TMM 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

@article{17c6127ac9c14ac598c71c6067943b61,

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.",

keywords = "Chemoradiation, Gene therapy, Head and neck cancer, Recurrent disease, Translational research",

author = "Seiwert, {T. Y.} and T. Darg and D. Haraf and Blair, {E. A.} and K. Stenson and Cohen, {E. E.W.} and Salama, {J. K.} and V. Villaflor and Witt, {M. E.} and Lingen, {M. W.} and Weichselbaum, {R. R.} and Vokes, {E. E.}",

note = "Funding Information: This study was supported by the NCI R01 CA113662 grant (RRW), an ASCO Translational Professorship (EEV), The Francis L. Lederer Foundation (EEV), as well as GenVec, Inc. Gaithersburg, MD.",

year = "2013",

month = mar,

doi = "10.1093/annonc/mds523",

language = "English (US)",

volume = "24",

pages = "769--776",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

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 - Seiwert, T. Y.

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.

N1 - Funding Information: This study was supported by the NCI R01 CA113662 grant (RRW), an ASCO Translational Professorship (EEV), The Francis L. Lederer Foundation (EEV), as well as GenVec, Inc. Gaithersburg, MD.

PY - 2013/3

Y1 - 2013/3

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.

KW - Chemoradiation

KW - Gene therapy

KW - Head and neck cancer

KW - Recurrent disease

KW - Translational research

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DO - 10.1093/annonc/mds523

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