RRx-001 Affects Multiple Toxicities in Patients Receiving Concomitant Chemoradiation for Head and Neck Cancers: Observations of the PREVLAR Phase II Trial

Abstract

PURPOSE Phase IIa trial results suggested that RRx-001, an nucleotide-binding domain-like receptor protein 3 inhibitor and nuclear factor erythroid 2–related factor 2 activator, attenuated severe oral mucositis (SOM) in patients treated with concomitant chemoradiation (CRT) for oral cancer (OC) and oropharyngeal cancer (OPC). Given the shared pathobiology of CRT injury among other exposed tissues, we initiated a secondary analysis of reported adverse events (AEs) to assess RRx-001's potential benefit on non-SOM regimen-related toxicities. METHODS PREVLAR was an open-label randomized trial that has been completed and published. Patients were treated with CRT for locally advanced OC or OPC. Arms 1-3 received doses of RRx-001 twice a week beginning 2 weeks before the start of CRT. Arm 2 (n = 11) received additional RRx-001 once during weeks 2 and 5. Arm 3 (n = 13) received RRx-001 once a week for the first 6 weeks of CRT. Arm 4 (n = 10) received CRT only. Patients received standard intensity modulated radiation therapy (daily fractions of 2-2.2 Gy/minimum cumulative dose of 55 Gy) plus cisplatin. Comprehensive toxicity assessment was based on reported AEs graded using Common Terminology Criteria for Adverse Events v5.0 and categorized with the Medical Dictionary for Regulatory Activities. A two-sided Fisher's exact test was performed to compare AE incidences between RRx-001 arms and standard of care in a secondary analysis of the data. Overall false-positive rate in Fisher's exact test was controlled via Hochberg's adjustment method. RESULTS Compared with the control cohort, patients receiving RRx-001 demonstrated fewer AEs attributable to their CRT regimen. Statistically significant differences in AE incidences favoring RRx-001 were dependent on the RRx-001 dosing regimen. CONCLUSION This secondary analysis suggests that RRx-001 infusion may reduce multiple, biologically related AEs associated with a standard CRT regimen. More broadly, it suggests that it is possible that agents that effectively target central pathobiology targets may mitigate more than one toxicity.