GC4419 reduces radiation-induced severe oral mucositis among patients with head and neck cancer
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The superoxide dismutase mimetic GC4419 appeared to safely and significantly reduce the duration, incidence and severity of radiation-induced severe oral mucositis compared with placebo among patients with head and neck cancer, according to results of a randomized phase 2b study published in Journal of Clinical Oncology.
“The current management options for mitigating oral mucositis include low-level laser therapy, various mouth rinses, barrier gels, topical anesthetics and systemic pain medications. None of the currently available options have shown enough statistical efficacy in the setting of chemoradiation for head and neck cancer to be FDA approved for that indication,” Carryn M. Anderson, MD, residency program director in the department of radiation oncology and clinical associate professor of radiation oncology at Carver College of Medicine at University of Iowa, told Healio. “Most of the options try to manage the pain from oral mucositis and do not impact the underlying pathophysiology of oral mucositis.”
Radiation-induced severe oral mucositis occurs by a biological cascade that initiates the formation of reactive oxygen species, including superoxide, according to study background. GC4419 (Galera Therapeutics) converts superoxide to hydrogen peroxide, thus thwarting initiation of the cascade.
“By saturating the cells with an IV infusion of the enzyme prior to each radiation treatment, the enzyme is readily available to convert the radiation-induced superoxide to hydrogen peroxide,” Anderson said. “Secondary enzymes in our normal cells rapidly convert the hydrogen peroxide to oxygen and water, thus sparing them from the toxicity of radiation. Malignant cells are deficient in the secondary enzymes and thus hydrogen peroxide builds up in the malignant cells and causes cell death.”
Results of a previous phase 1b/phase 2a trial showed reductions in severe oral mucositis incidence, duration and severity among patients with head and neck cancer who received GC4419 at doses of 30 mg or 90 mg before each intensity-modulated radiation therapy fraction as they underwent concurrent cisplatin.
The double-blind, multi-institutional phase 2b trial by Anderson and colleagues evaluated the efficacy and safety of GC4419 to reduce severe oral mucositis among 223 patients (median age, 57 years; range, 30-84; 86% men) with locally advanced oral cavity or oropharynx cancer. The researchers randomly assigned patients to receive GC4419 at a dose of 30 mg (n = 73) or 90 mg (n = 76) or placebo (n = 74) via 60-minute IV delivery before each intensity-modulated radiation therapy fraction.
Patients underwent intensity-modulated radiation therapy definitively or postoperatively in 2 Gy to 2.2 Gy fractions, for a total tumor dose of 60 Gy to 72 Gy, plus cisplatin at 80 mg/m² to 100 mg/m² every 3 weeks or 30 mg/m² or 40 mg/m² weekly.
Researchers assessed the severity of oral mucositis according to WHO grade biweekly during radiation therapy and weekly for up to 8 weeks after radiation was completed.
Duration of severe oral mucositis for each dose level vs. placebo served as the primary endpoint.
Results showed GC4419 administered at 90 mg significantly reduced the duration of severe oral mucositis compared with placebo (1.5 days vs. 19 days; P = .024). Researchers also observed reductions in incidence (43% vs. 65%; P = .009) and severity (grade 4 incidence, 16% vs. 30%; P = .045) of severe oral mucositis with the 90 mg GC4419 dose compared with placebo.
GC4419 at 30 mg induced intermediate improvements compared with placebo.
No significant GC4419-specific toxicities occurred across treatment arms, nor did the study treatment appear to increase the known toxicity of intensity-modulated radiation therapy with cisplatin. The most common adverse events related to GC4419 or cisplatin included grade 1 or grade 2 nausea (placebo, 75%; 30 mg GC4419, 68%; 90 mg GC4419, 82%) and vomiting (47% vs. 52% vs. 49%).
Possible associations between GC4419 and reduced need for narcotics requires further study, researchers acknowledged. Two-year follow-up for tumor outcomes was ongoing at the time of the report.
“The results of this phase 2b trial are certainly promising, but the phase 3 ROMAN trial must be completed to confirm the results,” Anderson said. “The ROMAN trial is currently open and enrolling in the US and Canada.”– by John DeRosier
For more information:
Carryn Anderson, MD, can be reached at Roy J. and Lucille A. Carver College of Medicine, Department of Radiation Oncology, 200 Hawkins Drive LL-W Pomerantz Family Pavilion, Iowa City, IA 52242-1089; email: carryn-anderson@uiowa.edu.
Disclosures: Galera Therapeutics funded this study. Anderson reports research funding to her institution from Galera Therapeutics and travel expenses from Elekta. Please see the study for all other authors’ relevant financial disclosures.
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