Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma

Carryn M. Anderson, Stephen T. Sonis, Christopher M. Lee, Douglas Adkins, Bryan G. Allen, Wenqing Sun, Sanjiv S. Agarwala, Madhavi L. Venigalla, Yuhchyau Chen, Weining Zhen, Diane R. Mould, Jon T. Holmlund, Jeffrey M. Brill, John M. Buatti

Research output: Contribution to journalArticle

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Abstract

Purpose: To assess the safety of the superoxide dismutase mimetic GC4419 in combination with radiation and concurrent cisplatin for patients with oral cavity or oropharyngeal cancer (OCC) and to assess the potential of GC4419 to reduce severe oral mucositis (OM). Patients and Methods: Patients with locally advanced OCC treated with definitive or postoperative intensity modulated radiation therapy (IMRT) plus cisplatin received GC4419 by 60-minute intravenous infusion, ending <60 minutes before IMRT, Monday through Friday for 3 to 7 weeks, in a dose and duration escalation study. Oral mucositis was assessed twice weekly during and weekly after IMRT. Results: A total of 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15 to 112 mg/d over 3 weeks (n=20), duration escalation in 3 cohorts receiving 112 mg/d over 4 to 6 weeks (n=12), and then 3 additional cohorts receiving 30 or 90 mg/d over 6 to 7 weeks (n=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of 2 separate cohorts at 112 mg. Nausea/vomiting and facial paresthesia during infusion seemed to be GC4419 dose–related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6 to 7 weeks, with median duration of only 2.5 days. Conclusions: The safety of GC4419 concurrently with chemoradiation for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM seemed less frequent and briefer than expected.

Original languageEnglish (US)
Pages (from-to)427-435
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume100
Issue number2
DOIs
StatePublished - Feb 1 2018

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Stomatitis
inorganic peroxides
Chemoradiotherapy
Superoxide Dismutase
vomiting
Mouth
Oropharyngeal Neoplasms
cancer
Carcinoma
dosage
cavities
nausea
Vomiting
radiation therapy
Radiotherapy
Paresthesia
toxicity
Nausea
Cisplatin
safety

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma. / Anderson, Carryn M.; Sonis, Stephen T.; Lee, Christopher M.; Adkins, Douglas; Allen, Bryan G.; Sun, Wenqing; Agarwala, Sanjiv S.; Venigalla, Madhavi L.; Chen, Yuhchyau; Zhen, Weining; Mould, Diane R.; Holmlund, Jon T.; Brill, Jeffrey M.; Buatti, John M.

In: International Journal of Radiation Oncology Biology Physics, Vol. 100, No. 2, 01.02.2018, p. 427-435.

Research output: Contribution to journalArticle

Anderson, CM, Sonis, ST, Lee, CM, Adkins, D, Allen, BG, Sun, W, Agarwala, SS, Venigalla, ML, Chen, Y, Zhen, W, Mould, DR, Holmlund, JT, Brill, JM & Buatti, JM 2018, 'Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma', International Journal of Radiation Oncology Biology Physics, vol. 100, no. 2, pp. 427-435. https://doi.org/10.1016/j.ijrobp.2017.10.019
Anderson, Carryn M. ; Sonis, Stephen T. ; Lee, Christopher M. ; Adkins, Douglas ; Allen, Bryan G. ; Sun, Wenqing ; Agarwala, Sanjiv S. ; Venigalla, Madhavi L. ; Chen, Yuhchyau ; Zhen, Weining ; Mould, Diane R. ; Holmlund, Jon T. ; Brill, Jeffrey M. ; Buatti, John M. / Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma. In: International Journal of Radiation Oncology Biology Physics. 2018 ; Vol. 100, No. 2. pp. 427-435.
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abstract = "Purpose: To assess the safety of the superoxide dismutase mimetic GC4419 in combination with radiation and concurrent cisplatin for patients with oral cavity or oropharyngeal cancer (OCC) and to assess the potential of GC4419 to reduce severe oral mucositis (OM). Patients and Methods: Patients with locally advanced OCC treated with definitive or postoperative intensity modulated radiation therapy (IMRT) plus cisplatin received GC4419 by 60-minute intravenous infusion, ending <60 minutes before IMRT, Monday through Friday for 3 to 7 weeks, in a dose and duration escalation study. Oral mucositis was assessed twice weekly during and weekly after IMRT. Results: A total of 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15 to 112 mg/d over 3 weeks (n=20), duration escalation in 3 cohorts receiving 112 mg/d over 4 to 6 weeks (n=12), and then 3 additional cohorts receiving 30 or 90 mg/d over 6 to 7 weeks (n=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of 2 separate cohorts at 112 mg. Nausea/vomiting and facial paresthesia during infusion seemed to be GC4419 dose–related. Severe OM occurred through 60 Gy in 4 of 14 patients (29{\%}) dosed for 6 to 7 weeks, with median duration of only 2.5 days. Conclusions: The safety of GC4419 concurrently with chemoradiation for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM seemed less frequent and briefer than expected.",
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AU - Sonis, Stephen T.

AU - Lee, Christopher M.

AU - Adkins, Douglas

AU - Allen, Bryan G.

AU - Sun, Wenqing

AU - Agarwala, Sanjiv S.

AU - Venigalla, Madhavi L.

AU - Chen, Yuhchyau

AU - Zhen, Weining

AU - Mould, Diane R.

AU - Holmlund, Jon T.

AU - Brill, Jeffrey M.

AU - Buatti, John M.

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N2 - Purpose: To assess the safety of the superoxide dismutase mimetic GC4419 in combination with radiation and concurrent cisplatin for patients with oral cavity or oropharyngeal cancer (OCC) and to assess the potential of GC4419 to reduce severe oral mucositis (OM). Patients and Methods: Patients with locally advanced OCC treated with definitive or postoperative intensity modulated radiation therapy (IMRT) plus cisplatin received GC4419 by 60-minute intravenous infusion, ending <60 minutes before IMRT, Monday through Friday for 3 to 7 weeks, in a dose and duration escalation study. Oral mucositis was assessed twice weekly during and weekly after IMRT. Results: A total of 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15 to 112 mg/d over 3 weeks (n=20), duration escalation in 3 cohorts receiving 112 mg/d over 4 to 6 weeks (n=12), and then 3 additional cohorts receiving 30 or 90 mg/d over 6 to 7 weeks (n=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of 2 separate cohorts at 112 mg. Nausea/vomiting and facial paresthesia during infusion seemed to be GC4419 dose–related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6 to 7 weeks, with median duration of only 2.5 days. Conclusions: The safety of GC4419 concurrently with chemoradiation for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM seemed less frequent and briefer than expected.

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