Phase 1b/2a Trial of Superoxide (SO) Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiation Therapy–Induced Oral Mucositis (OM) in Patients With Oral Cavity or Oropharyngeal Carcinoma (OCC)

Abstract

Seventy percent of patients (pts) with OCC develop severe OM (SOM) after a median 40-Gy radiation therapy (RT) treatment plus concurrent cisplatin (CDDP). There are no approved interventions to reduce the incidence or severity of OM. RT-induced SO is a key initiator of OM. GC4419’s (MW=483) specific mimicry of SOD’s dismutation of SO to H2O2 mitigated SOM in a translational hamster model. We hypothesized that GC4419 immediately prior to intensity modulated RT (IMRT) fractions would reduce incidence, severity, duration, and delay onset, of SOM. Serial 3 to 6 pt cohorts with locally advanced, nonmetastatic OCC were planned for definitive or post-op IMRT to approximately 70 Gy total (>50 Gy to ≥ 2 oral sites), 1.8 to 2.2 Gy/fx M-F plus CDDP; plus escalating doses of GC4419, over 60-min IV, M through F for 3 to 7 weeks, ending <60 min before IMRT. WHO grade OM was assessed twice weekly. GC4419 was measured in plasma. OM-related circulating cytokines (Cy) and changes in gene expression were assayed prior to and during treatment. Forty-six pts received GC4419; 43 were evaluable for OM at dose levels/d: 15 to 112 mg x 3 wks (n=20); 112 mg x 4 to 5+ wks (n=9); 30 mg x 7 wks (n=4); 90 mg x 6 weeks (n=4); 90 mg x 7 wks (n=6). Efficacy: SOM duration, incidence through 6 wks/60 Gy, severity, and onset appeared markedly improved from historical controls (Table 1); overall SOM incidence (50% vs 70%) was also reduced. GC4419 efficacy was related to treatment duration (Table 1), but not absolute daily dose. Safety: A true maximum tolerated dose was not reached. Gr 3 gastroenteritis and Gr 3 nausea/vomiting (1 each, 112 mg/d x 3 or 6 wks) were considered dose-limiting. Dose-related Gr 1-2 peri-infusional facial tingling was attributable to GC4419. Other AEs were consistent with known effects of IMRT/CDDP. PK: Dose-related Cmax and AUC; plasma t1/2 approximately 2 hours. Biomarkers: Cy levels were associated with GC4419 dose and WHO severity, consistent with known OM pathogenesis. When GC4419 was given throughout IMRT, SOM was less frequent, briefer, delayed, and less severe than expected. GC4419-related toxicity was mild-to-moderate and acceptable in combination with IMRT/CDDP. Doses of 30 and 90 mg/d were chosen for a future randomized, placebo-controlled trial.Abstract 11; Table 1SOM (Grades 3 and 4)Comparative historical control dataGC4419 treatmentMatched data setPlacebo data from phase 3 trials (JCO, 2011)3 weeks (15-112 mg/d)<6 weeks (15-112 mg/d)6-7 weeks (30 or 90 mg/d)S. SonisLe et alHenke et al# Patients≈3009494202914Incidence through 60 Gray60%57%62%40%41%28%Intensity: Grade 4 overall incidence20%19%26%25%31%0%Onset: Median days283532>54>50>50Duration: Median days2826224.592.5 Open table in a new tab