Avasopasem manganese treatment for severe oral mucositis from chemoradiotherapy for locally advanced head and neck cancer: phase 3 randomized controlled trial (ROMAN).

Background: Of patients who receive standard concomitant chemoradiation (CRT; intensity-modulated radiation therapy [IMRT] plus cisplatin) for locally advanced head and neck cancer (HNC), approximately two-thirds will develop severe oral mucositis (SOM), limiting their ability to eat solids (WHO grade 3) or drink liquids (WHO grade 4). In a randomized, double-blind phase 2b trial, avasopasem manganese substantially reduced duration and incidence of SOM versus placebo. This phase 3 trial further assessed avasopasem's reduction of SOM due to CRT. Methods: In this double-blind, placebo-controlled trial (Clinicaltrials.gov: NCT03689712), patients receiving 60-72 Gy IMRT (>50 Gy to ≥2 oral mucosal sites) plus cisplatin (Q3W or QW) were randomized 3:2 to avasopasem 90 mg or placebo before each RT fraction. SOM was assessed twice weekly during IMRT, then weekly for 2 weeks. First subject was enrolled 03 October 2018 and last subject completed OM follow-up 13 September 2021. Last subject completed long-term follow-up 30 August 2021. Primary endpoint was SOM incidence through end of IMRT. Secondary endpoints included SOM duration, time to onset, grade 4 incidence and duration, tumor outcomes, and renal function. Findings: 455 patients were randomized; 407 (241 avasopasem/166 placebo) were included in the primary analysis population. Statistically significant reductions in SOM incidence (54% vs 64%; relative risk = 0·84, Interpretation: The primary endpoint of incidence was not as improved as predicted by the Phase 2b trial and avasopasem's contribution to adverse events could not be excluded. For these reasons and others discussed, ROMAN did not provide a sufficiently favorable benefit-risk determination for FDA approval. A confirmatory phase 3 trial was requested. Funding: Provided by Galera Therapeutics, Inc.