Background: The results of an open-labeled Phase 2a trial suggested that infusion of RRx-001 (bromonitrozidine), a nitrogen-containing NLRP3 inhibitor and Nrf2 activator, attenuated the course and severity of SOM associated CRT (cisplatin/IMRT) in cancers of the mouth or OPC without impeding tumor response. The primary efficacy objectives of KEVLAR are to replicate the findings of the earlier trial and to determine if a higher dose of RRx-001 (8 mg x 4 doses prior to CRT) will favorably impact overall SOM incidence. Methods: KEVLAR is a planned Phase 2b study to be conducted at about thirty sites in North America. Approximately 216 patients with pathologically confirmed SCCs of the OC or OPC will be randomized equally into one of 3 cohorts: Arm 1 will receive RRx-001, 8 mg/dose infusions twice weekly during the 2 weeks prior to CRT start; Arm 2 will receive RRx-001, 4 mg/dose in the same schedule; Arm 3 will receive best supportive care only. All patients will receive intensity modulated radiation therapy (IMRT) in 2.0-2.2 Gy fractions/weekday to a cumulative radiation dose of up to 72 Gy. CRT must include cisplatin administered either weekly (40 mg/m²) or tri-weekly (100 mg/m²). Radiation fields must include at least two oral sites at SOM risk planned to receive at least 55 Gy. Mucositis indicators will be assessed twice weekly by trained evaluators. OM will be scored centrally using WHO criteria from the first day of CRT until resolution of ulcerative OM (WHO grade ≤1). Adverse events will be evaluated using NCICTCv5 criteria. Patients will be followed for 24 months post the last day of radiation and tumor response will be recorded quarterly using RECIST criteria.