Randomized Phase Ib Clinical Trial of DB-020 Intratympanic Injections to Reduce High-Dose Cisplatin Ototoxicity

Abstract

Purpose: This study evaluated DB-020, a formulation of thiosulfate for intratympanic (IT) injection, in patients receiving high-dose cisplatin chemotherapy.

Methods: This randomized phase Ib clinical trial enrolled patients older than 18 years from five centers in Australia and the United States scheduled for at least three cycles of cisplatin and total cumulative exposure of ≥280 mg/m². Patients received IT DB-020 (at a dose level of either 12% or 25%) in one ear and placebo in the other, once every 3 or 4 weeks, within 3 hours before receiving cisplatin. The primary end points were safety and tolerability, and the secondary end points included ototoxicity measured by air conduction audiometry. Ototoxicity was defined by American Speech-Language-Hearing Association criteria.

Results: Twenty-two patients with a median age of 55.1 years were randomly assigned and received a mean total cumulative cisplatin dose of 255 mg/m². Mean number of cisplatin cycles was 2.3. Twenty patients had both baseline and follow-up audiometry. Ear pain of short duration was common after IT injection. There were no persistent tympanic perforations and no serious adverse events in the category of ear and labyrinth disorders. A progressive reduction in patient numbers was observed at each cycle due to patients ceasing cisplatin treatment. DB-020 treatment did not affect plasma thiosulfate concentrations. Ototoxicity after cisplatin administration was significantly more common in placebo-treated ears than in DB-020-treated ears (DB-020 v placebo, P = .0027). The incidence of ototoxicity (250-8,000 Hz) was 85.0% in placebo-treated ears, and 54.5% and 22.2% in ears treated with DB-020 12% and DB-020 25%, respectively.

Conclusion: DB-020 IT injections were tolerated by patients and showed meaningful reductions in cisplatin ototoxicity.

FIG 1.

CONSORT diagram. ICF, informed consent form; LOCF, last observation carried forward; SAE, serious adverse event.

FIG 2.

Ototoxicity at LOCF: ASHA criteria applied to the 250-8,000 Hz frequency range. P = .0454 for DB-020 12% versus placebo and P = .0253 for DB-020 25% versus placebo using McNemar's test. ASHA, American Speech-Language-Hearing Association; LOCF, last observation carried forward.

FIG 3.

Mean audiogram plot for (A) placebo, (B) DB-020 12%, and (C) DB-020 25%. Mean hearing levels at baseline and LOCF for frequencies of 250-16,000 Hz. LOCF, last observation carried forward.