Background: Hearing loss (HL) as a result of cisplatin (CP) chemotherapy is common. DB-020 is a formulation of sodium thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. This phase 1 study was designed to evaluate safety and tolerability of repeated IT injections of DB-020 and compare CP-induced hearing changes with DB-020 vs placebo. Methods: Patients scheduled for at least three cycles of CP and cumulative exposure of ≥280 mg/m² were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other ear, once every 3 or 4 weeks, ≤3 hours before receiving CP. Patients naïve to CP with moderate or severe HL at baseline were excluded. Ototoxicity was defined by American Speech-Language-Hearing criteria: ≥20 dB threshold increase at any one test frequency, or ≥10 dB threshold increase in any two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously obtained. Severe ototoxicity was defined as ≥20 dB threshold increase in any two adjacent frequencies. Pre-specified analyses evaluated safety, ototoxicity (with McNemar’s test using the last observation carried forward), and average threshold shifts (from air conduction audiometry, analyzed with a mixed model with repeated measures). This is the final analysis of the data set following the interim analysis presented in 2023. Results: Twenty-two patients were randomized with a mean age of 55 years (86% male; 100% white). Pre-DB-020 treatment, mean cumulative CP dose was 255 mg/m², and 95% had head and neck cancers; 5% had lung cancer. Twenty patients had both baseline and follow-up audiometry, and 18/20 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels (overall mean cumulative CP dose was 254.7 mg/m²) were similar to reference values. Acute or temporary ear pain (18/22 patients, 82%), and tinnitus (11/22 patients, 50%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus in placebo treated ears. No persistent tympanic perforations, no serious adverse events in the ear and labyrinth disorders category, and no deaths were reported. Ototoxicity was significantly more common and severe in placebo treated ears. Conclusions: In this initial clinical trial experience, there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in CP-induced ototoxicity. Clinical trial information: NCT04262336.

LS, least squares.