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

Abstract Purpose Oral mucositis (OM) remains a critical problem; 70% of patients receiving chemoradiation (CRT) for oral cavity or oropharynx cancers (OCC) develop severe OM. Superoxide (O 2 •-) generated by CRT plays a significant role in initiating OM. Pre-clinical studies demonstrated that conversion of (O 2 •-) to O 2 and H 2 O 2 by the superoxide dismutase mimetic GC4419 interdicts this essential step. We hypothesized that GC4419 could safely be administered with CRT and reduce severe OM. Patients and Methods Patients with locally-advanced OCC treated with definitive or post-operative intensity-modulated (IM)RT plus cisplatin received GC4419 by 60-minute IV infusion, ending Results 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15-112 mg/day over 3 weeks (N=20); duration escalation in 3 cohorts receiving 112 mg/day over 4-6 weeks (N=12), then 3 additional cohorts receiving 30 or 90 mg/day over 6-7 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 two separate cohorts @112 mg. Nausea/vomiting and facial paresthesia during infusion appeared to be GC4419 dose-related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6-7 weeks, with median duration of only 2.5 days. Conclusion Safety of GC4419 concurrently with CRT 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 appeared less frequent and briefer than expected.