Protection of chemo-radiation therapy induced oral mucositis (OM) in pre-clinical and clinical studies

Abstract

5567 Background: D-methionine, was shown to selectively protect normal but not tumor cells from loss of mitochondrial integrity and viability in response to ionizing radiation. OM is a debilitating complication of radiotherapy (RT) and chemotherapy (CT). MRx-1024, a orally bio-available formulation of this agent was evaluated as a treatment for the protection of OM. Methods: A mouse model of radiation-induced lip erythema was used to evaluate the efficacy of MRx-1024. Pharmacokinetic profile of MRX-1024 in healthy human volunteers as well as evaluation of oral MRX-1024 was accomplished in patients (pts) with head and neck cancer receiving RT or RT+CT. Pts received 1.8–2.0 Gy of RT daily for 5 days each week, to a total of 60 Gy. Selected pts also received cisplatin, 50mg/m2 weekly. MRX-1024 suspension was given 1 hour before and again after each RT fraction. Pts were evaluated weekly using 4 accepted scales for assessing OM. Results: A significant protection of radiation-induced lip erythema was achieved in pre-clinical studies without compromising tumor control. Plasma concentrations of MRx-1024 achieved in normal volunteers after oral administration were similar to those required for efficacy in pre-clinical studies. No major adverse events were attributed to MRx-1024. The incidence of OM from 21 evaluable pts was compared with historical controls from the same institution. MRX-1024 was found to be a safe, easily administered and well-tolerated agent that completely ameliorated the incidence of Grade 4 (21% in historical controls) and reduced the incidence of Grade 3 by 80% over historical controls. In addition, preliminary analysis indicated that MRX-1024 did not compromise antitumor activity. Conclusions: These pre-clinical and clinical studies provide exciting proof of principle evidence for the use of MRx-1024 in the treatment of OM. Follow-up clinical studies are underway to further validate these results. [Table: see text]