Background: Oral mucositis (OM) is a debilitating side effect of concomitant chemoradiotherapy (CRT) for head and neck cancer (HNC). EC-18 may effectively mitigate OM by minimizing the CRT-induced innate immune response. This Phase II, 2-stage trial evaluated safety, tolerability, and efficacy of EC-18 in reducing the duration, incidence, and trajectory of severe OM (SOM) in HNC patients. Methods: Patients (n = 105) with pathologically confirmed oral cavity, oropharynx, hypopharynx, or nasopharynx squamous cell cancers who received intensity-modulated radiation therapy (IMRT; with ≥ 55 Gy on ≥ 2 oral sites) and weekly or tri-weekly cisplatin were studied. In Stage 1, 24 patients were randomized (n = 6 per arm) to receive 500, 1000, or 2000 mg of EC-18, or placebo. Following independent Data Safety Monitoring Board review, 81 patients in Stage 2 received EC-18 2000 mg (n = 41) or placebo (n = 40) throughout CRT. WHO OM grade was assessed twice weekly during IMRT and then once weekly for up to 6 weeks post-IMRT. The primary efficacy endpoint was duration of SOM during the active and short-term follow-up (STFU) periods in the compliant per-protocol population (PP). Much of Stage 2 was conducted during peak periods of the COVID-19 pandemic which measurably impacted patient compliance relative to test medication dosing and planned radiation. Consequently, to assess efficacy most accurately, the PP population was analyzed (with at least 4 weeks of study drug dosing, minimum cumulative radiation of 55 Gy, 80% study drug compliance in the first 28 days of dosing, and without using not-allowed-therapy). Results: Patient demographics and baseline characteristics were balanced between groups. Adverse events (AEs) were comparable amongst cohorts without drug-related severe AEs. In the PP, the median duration of SOM from baseline through STFU was 0 day in the EC-18 group (n = 22) v 13.5 days in the placebo group (n = 20). SOM incidence through STFU (45.5% v 70%) and opioid use (time to onset: 32.3 v 26.0 days; and duration: 32.8 v 37.5 days) favored EC-18 v placebo. Results of the covariates analyses suggested that EC-18 favorably impacted SOM incidence in patients who experienced SOM treated with weekly low-dose cisplatin (n = 26; 37.5% v placebo 70.0%) and HPV+ tumors (n = 29; 35.3% v placebo 66.7%; Table). One-year long-term follow-up for tumor outcomes is ongoing. Conclusions: EC-18 safely mitigated the development and the time course of SOM in CRT-treated HNC patients. In addition, EC-18 may provide substantial benefits to subpopulations of HPV⁺ HNC patients treated with low dose cisplatin. Clinical trial information: NCT03200340.

*One unknown HPV status.