ROMAN: Phase 3 trial of avasopasem manganese (GC4419) for severe oral mucositis (SOM) in patients receiving chemoradiotherapy (CRT) for locally advanced, nonmetastatic head and neck cancer (LAHNC).

6005 Background: Intensity-modulated radiotherapy (IMRT) plus cisplatin is an established treatment for LAHNC, but ̃70% of patients develop SOM (WHO grade 3 or 4), limiting their ability to eat solids (grade 3) or liquids (grade 4), and often requiring nutrition by feeding tube. Management focuses on symptoms and supportive care (Elad 2020). There are no US-approved drugs to reduce SOM in LAHNC. A radiotherapy (RT)-induced burst of superoxide initiates oral mucositis (OM) development (Sonis 2004). Avasopasem (GC4419, AVA) is an investigational selective small molecule dismutase mimetic designed to convert superoxide to hydrogen peroxide, which may protect normal cells from, and potentially sensitize cancer cells to, radiation (Riley DP 2006, El-Mahdy 2020). In a randomized, double-blind phase 2b trial, AVA reduced duration and incidence of SOM due to CRT for LAHNC vs placebo (PBO) (Anderson 2019). The present trial (NCT03689712) further assessed safety and efficacy of AVA to reduce SOM due to CRT for LAHNC of the oral cavity (OC) or oropharynx (OP). Methods: Double-blind, PBO-controlled trial; patients receiving 60-72 Gy of IMRT (>50 Gy to ≥2 oral mucosal sites) plus cisplatin (weekly or q3 weeks) were randomized 3:2 to AVA 90 mg vs PBO by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators biweekly during RT & weekly for 2 weeks thereafter. Primary endpoint: SOM (WHO grade 3 or 4) incidence through the end of IMRT. Secondary endpoints included SOM duration through 2 weeks post-IMRT and grade 4 OM incidence through the end of IMRT. Results: N = 407 (241 AVA/166 PBO); median age 61; 86% male; 82% OP. Statistically significant 16% relative reduction in SOM incidence (54% vs 64%; p = 0.045) and 56% relative reduction in SOM duration (median, 8 vs 18 days; p = 0.002) were observed. Grade 4 incidence was reduced 27% ( p = 0.052). Improvement was seen in multiple secondary and exploratory endpoints (table). Adverse event frequencies (all grade, grade 3+, serious) were comparable between treatment groups without clear AVA-specific toxicity or increase in cisplatin-attributable toxicity. Conclusions: AVA produced statistically significant, clinically meaningful improvement of SOM vs PBO that was consistent across multiple measures of SOM, and was well tolerated, with an adverse event profile consistent with expectations for IMRT/cisplatin in LAHNC. Clinical trial information: NCT03689712. PBO AVA AVA vs PBO Relative Δ p value SOM incidence through IMRT 64% 54% 16% 0.045* SOM duration through f/u, median days 18 8 56% 0.002* Gr 4 OM incidence through IMRT 33% 24% 27% 0.052 SOM incidence through 50 Gy 45% 28% 38% < 0.001 SOM incidence through 60 Gy 58% 42% 28% 0.002 SOM incidence through f/u 71% 58% 18% 0.012 SOM onset, median days 38 49 29% 0.002 *statistically significant.

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