Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer

J Clin Oncol. 2019 Dec 1;37(34):3256-3265. doi: 10.1200/JCO.19.01507. Epub 2019 Oct 16.


Purpose: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM).

Patients and methods: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading.

Results: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing.

Conclusion: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; identifier: NCT03689712) has begun.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Chemoradiotherapy / adverse effects*
  • Chemoradiotherapy, Adjuvant / adverse effects*
  • Cisplatin / administration & dosage*
  • Cisplatin / adverse effects
  • Double-Blind Method
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / epidemiology
  • Mouth Neoplasms / pathology
  • Ontario
  • Organometallic Compounds / therapeutic use*
  • Oropharyngeal Neoplasms / drug therapy*
  • Oropharyngeal Neoplasms / epidemiology
  • Oropharyngeal Neoplasms / pathology
  • Radiation Injuries / diagnosis
  • Radiation Injuries / epidemiology
  • Radiation Injuries / prevention & control*
  • Radiation-Protective Agents / adverse effects
  • Radiation-Protective Agents / therapeutic use*
  • Radiotherapy, Intensity-Modulated / adverse effects*
  • Risk Factors
  • Severity of Illness Index
  • Stomatitis / diagnosis
  • Stomatitis / epidemiology
  • Stomatitis / prevention & control*
  • Time Factors
  • Treatment Outcome
  • United States


  • Antineoplastic Agents
  • Organometallic Compounds
  • Radiation-Protective Agents
  • avasopasem manganese
  • Cisplatin

Associated data