Results of a randomized, placebo (PBO) controlled, double-blind P2b trial of GC4419 (avisopasem manganese) to reduce duration, incidence and severity and delay onset of severe radiation-related oral mucositis (SOM) in patients (pts) with locally advanced squamous cell cancer of the oral cavity (OC) or oropharynx (OP).

Abstract

6006 Background: Intensity-modulated radiotherapy (IMRT) plus cisplatin 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). Methods: 223 pts with OC or OP cancer receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus cisplatin (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 biw during RT & qwk for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM. Analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α = 0.05. Results: 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration. Efficacy results with 30 mg were intermediate and did not reach significance. Baseline patient & tumor characteristics, & treatment delivery, were well-balanced. Safety was comparable across arms with no significant GC4419-specific toxicity or increased toxicity of IMRT/cisplatin. Conclusions: GC4419 provides a clinically meaningful reduction of SOM in terms of duration, incidence and severity (Grade 4), with a safety profile comparable to placebo. Clinical trial information: NCT02508389. PBO 30mg 90mg 90mg vs. PBO N 74 73 76 Relative δ p = Duration SOM, median days 19 8 1.5 92% 0.024 Incidence SOM thru 60 Gy 58% 40% 37% 36% 0.010* Incidence SOM thru last RT 65% 60% 43% 34% 0.009* Incidence Grade 4 OM 30% 21% 16% 47% 0.045* Onset SOM, median days 39 47 61 56% 0.080* *nominal p value, pre-specified secondary endpoint