A Dose-Escalation Phase Ib International Study to Evaluate the Safety, Pharmacokinetics and Efficacy of ST-617 for the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for H&N Cancer

Abstract

Oral Mucositis (OM) is a common, painful, and costly toxicity associated with cytotoxic chemoradiation regimens used to treat H&N cancer, which may interfere with planned treatment and negatively impact tumor control. There are currently no approved interventions to mitigate the incidence, severity or duration of OM. Oxidative stress is a critical event in OM's pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM. The objective of this trial was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of ST-617 in patients at high risk of severe OM (SOM).A dose escalation trial was performed in which ST-617, administered as an oral suspension, 1-2 hours before the administration of daily RT fractions at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily concomitant with BSC (Best Supportive Care) until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells.17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. As overall SOM incidence (baseline to the last day of radiation) of 50% was less than expected and was related to ST-617 dose: 50 mg/day 83% (n = 6); 100 mg/day 33% (n = 9); 200 mg/day 33% (n = 3). The 100 mg/day dose was well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM were noted Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. ST-617 did not alter tumor response at 1 year post-CRT (n = 17).ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. A dose-response effect on SOM incidence was noted. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day.