Pilot Study of the Antitumor Efficacy and Tolerability of Orally Administered Rrx-001 in Normal and Tumor-Bearing Mice

Purpose RRx-001 is a novel anticancer drug that will be entering Phase III clinical trials as a pre-sensitizer or resensitizer to chemotherapy and radiotherapy. To date, it has been very well tolerated, with the main adverse event being infusion-related reactions, consisting primarily of discomfort, itching and tingling at the site of infusion. The purpose of this preclinical pilot study was to study the antitumor efficacy and tolerability of oral administration of RRx-001 in a preclinical mouse model. Methods The maximum tolerated dose (MTD) of oral administration of RRx-001 was studied in normal C3H mice. For antitumor efficacy study, mice bearing SCC VII tumors were administered by oral gavage with RRx-001 either alone or in combination with external beam radiation therapy. Tumor growth delay time and body weight were used as the endpoints for antitumor efficacy and systemic toxicity. Results The estimated MTD for oral RRx-001 in 10% dimethyl sulfoxide (DMSO) daily for 5 days was 10-20 mg/kg. In tumor-bearing mice, oral dosing of RRx-001 at a total equivalent dose of 60 mg/kg, given either daily, or every other day, or as a single dose, significantly inhibited tumor growth (p < 0.01 vs. vehicle control). There were no statistically significant differences in tumor growth delay time among three treatment regimens (P > 0.05). However, a single dose of 60 mg/kg caused a 28% modality (2 death among 7 treated mice). When combined with local tumor radiation therapy, oral RRx-001 significantly increased the antitumor efficacy of radiation therapy (p = 0.02, combination vs. radiation alone). There were no obvious systemic or additional toxicities for combination of oral RRx-001 (10-20 mg/kg) and radiation therapy. Conclusion Oral administration of RRx-001 was safe and effective in the SCC VII tumor model in mice, and merits further study.