A phase 1 clinical trial of DB-020 intratympanic injections administered prior to high dose cisplatin chemotherapy to reduce ototoxicity.

person Danny Rischin Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia info_outline Danny Rischin, Stephen John O'Leary, Christopher David Hart, Chandra Sai Diwakarla, Nagashree Seetharamu, John Lee, Shane Raines, Tera Quigley, Heather M Wolff, Pablo Lapuerta, Benedict J Panizza

Authors person Danny Rischin Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia info_outline Danny Rischin, Stephen John O'Leary, Christopher David Hart, Chandra Sai Diwakarla, Nagashree Seetharamu, John Lee, Shane Raines, Tera Quigley, Heather M Wolff, Pablo Lapuerta, Benedict J Panizza Organizations Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, The University of Melbourne, Melbourne, Australia, St. Vincent's Hospital Melbourne, Fitzroy, Australia, Royal Perth Hospital, Nedlands, Australia, Northwell Health, New Hyde Park, NY, Decibel Therapeutics Inc, Boston, MA, 2b Analytics, LLC, Wallingford, PA, Decibel Therapeutics, Boston, MA, Lapuerta Consulting, LLC, Skillman, NJ, Princess Alexandra Hospital and Faculty of Medicine at University of Queensland, Woolloongabba, QLD, Australia Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Decibel Therapeutics Background: Hearing loss with cisplatin (CP) chemotherapy is common. DB-020 is a formulation of thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. The primary objective of this Phase 1 study was to evaluate the safety and tolerability of repeated IT injections of DB-020. A secondary objective was to compare hearing changes with DB-020 vs. placebo. Methods: Subjects scheduled for at least 3 cycles of CP and cumulative exposure of ≥280 mg/m 2 were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other, once every 3 or 4 weeks, up to 3 hours before receiving CP. Subjects with moderate or severe hearing loss 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 ≥20 dB threshold increase in any two adjacent frequencies. A pre-specified interim analysis 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). Results: Nineteen subjects were randomized, with mean age of 57 years (84% male and 100% white) and mean cumulative CP dose 248 mg/m 2 . Most (95%) had head and neck cancers (5% had lung cancer). Seventeen subjects had both baseline and follow-up audiometry, and 16/17 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels were similar to reference values. Ear pain (15/19 subjects, 78.9%) and tinnitus (8/19 subjects, 42.1%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus was more common in placebo treated ears. There were no tympanic perforations, no serious adverse events in the category of ear and labyrinth disorders, and no deaths. Ototoxicity was significantly more common and more severe in placebo treated ears (Table). As the overall study objectives were met at this interim analysis, no further enrollment was pursued. Conclusions: In this initial clinical trial experience there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in cisplatin ototoxicity. These results warrant further clinical development. Clinical trial information: NCT04262336. Assessment Placebo ears (n=17) DB-020 ears (n=17) p-value vs. placebo Ototoxicity (250 to 8000 Hz) 88.2% 41.2% 0.0047 Ototoxicity (9000 to 16000 Hz) 88.2% 52.9% 0.0143 Severe ototoxicity (250 to 8000 Hz) 64.7% 11.8% 0.0027 Severe ototoxicity (9000 to 16000 Hz) 76.5% 29.4% 0.0047 Acoustic threshold shift (LS mean dB), 250 to 8000 Hz 15.27 4.35 0.001 Acoustic threshold shift (LS mean dB), 9000 to 16000 Hz 18.23 8.45 0.010

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