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

Abstract

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; ClinicalTrials.gov identifier: NCT03689712) has begun.

Figures

FIG 1.

CONSORT diagram: patient random assignment. ITT, intent to treat.

FIG 2.

Cumulative severe oral mucositis (WHO grade 3 or 4) incidence (%) at progressive intensity-modulated radiation therapy delivery landmarks (Gray cutoffs).

FIG 3.

Swimmer plot of severe oral mucositis scores for the subsets of patients in (left) the placebo arm (n = 45) or (right) the 90-mg arm (n = 35) who had at least one WHO oral mucositis score of grade 3 or 4. Each horizontal lane represents the experience of an individual patient. Time on radiation therapy or after radiation therapy is indicated at the top, for which the vertical line denotes the end of intensity-modulated radiation therapy. Yellow, WHO grade 3; red, WHO grade 4; purple, WHO grade 0 to 2. WHO scoring was done twice per week during radiation therapy, then once per week after radiation therapy in patients who returned for follow-up for up to 8 weeks or until the WHO score was 0 or 1.

FIG A1.

Numbers of patients with grade 4 oral mucositis of progressively greater length, 90 mg v placebo.