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.

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.

Mouse strain and quality control testing: improved sensitivity of the mouse embryo assay with embryos from outbred mice.

OBJECTIVE: To determine the relative sensitivities of embryos from different strains of mice to in vitro stress. DESIGN: Laboratory experiment with embryos from different mouse strains. SETTING: University hospital-based fertility clinic. ANIMAL(S): Mice. INTERVENTION(S): Fresh one-cell embryos from outbred (CF1), inbred (FVB), F1 hybrid (B6/CBA), and cryopreserved F2 hybrid embryos (bcl/B6 × B6/bcl) compared in a mouse embryo assay (MEA) using six doses of each of three in vitro stressors: cumene hydroperoxide in mineral oil, Triton X-100 (TX-100) in media, and hyperosmolality. MAIN OUTCOME MEASURE(S): Blastocyst rate at 96 hours. RESULT(S): All studies were conducted in triplicate; data were analyzed with chi-square analysis based on fitting a logistic regression model. Both cumene hydroperoxide and Triton X-100 affected blastocyst formation in the outbred strain at concentrations that were less than half of the concentration that affected the other strains. The total number of cells was affected by the treatments in all strains. CONCLUSION(S): Outbred CF1 embryos are genetically diverse and more sensitive to toxins than either inbred or hybrid mouse embryos. Outbred embryos provide an additional tool for effective quality-control testing.