Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients

Abstract

Cisplatin is a widely used chemotherapy for the treatment of certain solid tumors. Ototoxicity and subsequent permanent hearing loss remain a serious dose-limiting side effect associated with cisplatin treatment. To date, no therapies have been approved to prevent or treat cisplatin-induced hearing loss (CIHL). Sodium thiosulfate effectively inactivates cisplatin through covalent binding and may provide protection against cisplatin-induced ototoxicity. DB-020 is being developed as a novel formulation of sodium thiosulfate pentahydrate in 1% sodium hyaluronate for intratympanic injection (IT), enabling the delivery of high concentrations of thiosulfate into the cochlea prior to cisplatin administration. In the DB-020-002 phase 1a single-ascending dose study, healthy volunteers were enrolled into 5 cohorts to receive different doses of DB-020 via IT injection. Cohorts 1-4 received unilateral injections while Cohort 5 received bilateral injections. Plasma thiosulfate pharmacokinetics was measured, and safety and audiometric data were collected throughout the study. This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the design and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy.

Keywords: Cisplatin; Hearing loss; Intratympanic; Ototoxicity.

Fig. 1

Study Schema. Cohorts 1–4 included 8 subjects randomly assigned (3:1) to receive either DB-020 (6 subjects) or placebo (2 subjects). The ear to be injected was randomly assigned. Subjects in Cohorts 1–4 received a unilateral injection. Subjects in Cohort 5 received bilateral injections (both ears receiving the same study drug as randomized) and 10 subjects were enrolled (1 subject received placebo). The dose in Cohort 5 was selected following review of safety and tolerability observed in the unilateral cohorts

Fig. 2

Human plasma thiosulfate levels following DB-020 IT administration. (a) Human plasma thiosulfate levels over 0 to 24 h following IT administration of DB-020, cohorts 1–5. (b) Human plasma thiosulfate levels over 0 to 672 h (28 days) following IT administration of DB-0202, cohorts 1–5. (c) Human plasma thiosulfate levels over 0 to 4 h following IT administration of DB-020, cohorts 1–5. (d) Human plasma thiosulfate levels over 0 to 4 h following IT administration of DB-020, cohorts 1–5 in relation to the concentration of thiosulfate that should have no impact on cisplatin cell killing (ie 30 uM)