A Randomized, Placebo (Pbo) Controlled, Double-Blind P2b Trial Of Gc4419 (Avisopasem Manganese) To Reduce Severe Radiation-Related Oral Mucositis (Som) In Patients (Pts) With Locally Advanced Squamous Cell Cancer Of The Oral Cavity (Oc) Or Oropharynx (Op)

Intensity-modulated radiation therapy (IMRT) plus cisplatin (CDDP) is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring artificial nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by potently converting superoxide to H2O2. It showed promising reductions of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). Hypothesis: GC4419 reduces SOM without increasing toxicity or decreasing tumor control of IMRT/CDDP. A total of 223 pts with OC or OP cancers receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus CDDP (qwk or q3wk), were randomized 1:1:1 to PBO, 30 or 90 mg of GC4419, by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators during RT & for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM, & safety. Efficacy analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α=0.05. Baseline patient & tumor characteristics were balanced: 86% M, 77% OP, 77% definitive, 82% IVa, 34% T4, 72% HPV+, 38% q3wk CDDP, number of oral sites receiving ≥ 50 Gy [3-4 sites; 53%; 5+ sites, 38%]); as was treatment delivery (median 70 Gy; 6% had RT breaks ≥ 5 consecutive fractions; 80% received ≥ 200 mg/m2 CDDP; 87% received ≥ 80% of planned GC4419/PBO doses). 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration (TABLE). Cumulative SOM incidence throughout RT (i.e., through 30, 40, 50 Gy) was also consistently lower with 90 mg GC4419 v PBO. Safety was comparable across arms with no significant GC4419-specific toxicity; chemotherapy toxicity of IMRT/cisplatin did not appear to be increased. 2-year follow up for tumor outcomes is in progress. GC4419 90 mg produced a clinically meaningful reduction of SOM; the primary analysis (duration) was statistically significant. Efficacy results with 30 mg were intermediate and did not reach significance. The safety profile was comparable to placebo. Interim tumor control data and exploratory correlative analyses will be presented.Abstract 223; TableNPBO30mg90mg90mg vs. PBO747376Relative δp-valueDuration SOM, median days1981.592%0.024Incidence SOM thru 60 Gy58%40%37%36%0.010*Incidence SOM thru last RT65%60%43%34%0.009*Incidence Grade 4 OM30%21%16%47%0.045*Onset SOM, median days39476156%0.080**nominal p value, pre-specified secondary endpoint Open table in a new tab