Scottsdale, AZ—The superoxide dismutase mimetic GC4419 markedly reduced the incidence, intensity, and duration of severe oral mucositis in a study of patients with head and neck cancer, according to Carryn Anderson, MD, Clinical Assistant Professor, Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, and colleagues.1
Among patients with oropharyngeal carcinoma, 70% develop severe oral mucositis, usually about 3 to 4 weeks after treatment with median 40-Gy radiation therapy (RT) and concurrent cisplatin. Currently, there are no approved interventions for reducing the incidence or severity of oral mucositis.
“We know that radiation induces a superoxide burst that initiates a downstream cascade of events leading to oral mucositis,” explained Dr Anderson. “GC4419 is a dismutase mimetic that is selective for converting superoxide into hydrogen peroxide. This translates to protect normal tissue from the consequences of a radiation-induced superoxide burst.”
In multiple preclinical trials, this drug has not protected tumors from the cytotoxic effects of RT or chemotherapy. “In fact, it creates an environment that is selectively more toxic to cancer cells by increasing hydrogen peroxide,” she said.
Dr Anderson and her coinvestigators sought to evaluate the efficacy of GC4419 in reducing chemoradiotherapy-induced oral mucositis in patients with oral cavity or oropharyngeal carcinoma, and presented results of their phase 1b/2a trial at the 2016 Multidisciplinary Head and Neck Cancer Symposium.
Patient Population and Treatment Methods
Patients with locally advanced oral cavity or oropharynx cancer were enrolled in a 3 plus 3 serial cohort, with a dose-escalation design. Patients were scheduled for definitive or post-op intensity-modulated RT (IMRT) to a minimum of 50 Gy total to ≥2 oral sites, plus escalating doses of GC4419 administered via intravenous infusion over 60 minutes, ending <60 minutes before each IMRT fraction.
World Health Organization grade oral mucositis measurements were taken twice weekly, and assessed once weekly in the 8 weeks following treatment completion; tumor follow-up was conducted for 1 year post-IMRT.
Nine centers in the United States participated; the study population consisted mostly of men (n = 38; median age, 58 years), and the majority were human papillomavirus–positive patients with oropharynx cancer treated with concurrent chemoradiation therapy.
Severe Oral Mucositis Delayed, and Less Frequent, Severe
A total of 46 patients received GC4419, of which 43 were evaluable. Patients received doses of GC4419 from 15 mg to 112 mg over the course of 3 to 7 weeks. At 112 mg, grade 3 nausea and vomiting were observed; therefore, the investigators reduced the doses to 30 mg and 90 mg, given over 6 to 7 weeks.
GC4419 was found to have an acceptable safety profile; the most common adverse events observed were typical of patients receiving concurrent chemotherapy and radiation. No formal maximum tolerated dose of GC4419 was reached with this trial, but dose-limiting toxicities did occur at 112 mg. Some patients experienced mild, transient facial tingling that occurred during the infusion, and subsequently resolved after the infusion was completed.
“Most importantly, we are seeing no evidence of tumor protection in our follow-up to date, with 24 patients having reached 1 year of follow-up,” Dr Anderson reported. “And when we look closer at our full treatment regimen patients that received the 90 mg and 30 mg doses of GC4419 over the 6 to 7 weeks, we see that the onset of severe oral mucositis is delayed, its duration is shorter, its incidence is lower, and we did not see any grade 4 toxicities in these patients,” she said.
Randomized Controlled Trial Underway
The investigators found that GC4419 not only decreases severe oral mucositis, but also improves upon all grades of oral mucositis. “As [GC4419] scheduled over 3, 4, 5, and 6 to 7 weeks of therapy, you can see that [oral mucositis] duration is decreased with the increase in the dosing schedule,” she said.
Dr Anderson added that an oral version of the drug is in development, and GC4419 doses of 30 mg and 90 mg a day were chosen for a phase 2, randomized, placebo-controlled, double-blind trial that is currently underway.
1. Anderson CM, Allen BG, Sun W, et al. Phase 1b/2a trial of superoxide (SO) dismutase (SOD) mimetic GC4419 to reduce chemoradiation therapy-induced oral mucositis (OM) in patients with oral cavity or oropharyngeal carcinoma (OCC). Presented at: Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ. www.redjournal.org/article/S0360-3016(15)26871-X/pdf. Accessed April 11, 2016.