Secondary Analysis of RRx-001 on the Incidence of Related Toxicities in Patients Treated with Concomitant Chemoradiation for Locally Advanced Head and Neck Cancer

Abstract

The results of an open-labeled Phase 2a trial (PREVLAR) suggested that infusion of RRx-001 (bromonitrozidine), a nitrogen-containing NLRP3 inhibitor and Nrf2 activator, attenuated the course and severity of severe oral mucositis (SOM) associated CRT (cisplatin/IMRT) in cancers of the mouth or OPC without impeding tumor response.1 Given its mechanism of action and the shared biology of radiation injury pathogenesis among other exposed tissues, we investigated the potential halo effect of RRx-001 on other regimen-related toxicities. PREVLAR was a multi-center, open-label randomized trial in which patients (n = 46) having locally advanced, histologically confirmed SCC of the OC or OPC were centrally randomized to one of four arms. Arms 1-3 received 2 weekly doses of RRx-001 (4 mg/dose) beginning 2 weeks before the start of CRT. Arm 2 (n = 11) received 2 additional RRx-001 infusions during weeks 2 and 5 and patients in Arm 3 (n = 13) received weekly RRx-001 for the first 6 weeks of CRT. 10 mg of dexamethasone was administered before RRx-001 infusions. Arm 4 (n = 10), the control, received CRT only. Adverse events (AEs) were assessed using CTCAE v5. All patients received standard regimens of IMRT (daily fractions of 2-2.2 Gy/minimum cumulative dose of 55 Gy) plus either weekly or tri-weekly cisplatin. Consistent with the observation that RRx-001 was most efficacious in attenuating the course of SOM when administered only prior to CRT (Arm 1) or prior to CRT with additional dosing on weeks 2 and 5 (Arm 2), compared to Arm 3 or control, the same dosing schedule appeared to be impactful on signs and symptoms of radiation-associated damage with tissues such as salivary glands and skin (Table 1). In particular, compared to control patients, patients in Arms 1 and 2 had a lower incidence of dry mouth (none vs. 60%), dysphagia (none vs. 70%), salivary duct inflammation (none vs. 30%), candida infection (9.1% vs 40%), radiation associated skin injury (Arm 1 none, Arm 2 18.2%, control 70%) and weight loss (none vs. 50%) as examples. In this small proof of concept trial, RRx-001 infusion resulted in a reduction of multiple, biologically-related, side effects associated with a standard chemoradiation regimen used to the treatment of head and neck cancers. KEVLAR, a larger Phase 2b trial is planned to begin enrollment in Q4 of 2023 at about thirty sites in North America.