Feasibility and Safety of Intratympanic Administration of Sustained-Exposure Dexamethasone Thermosensitive Gel (OTO-104) for Prevention of Cisplatin-Induced Hearing Loss in Children: A Multisite Phase 2 Randomized Clinical Trial

David R Freyer^{1

2}, Timothy J D Ohlsen^{3

4}, Debra Don⁵, Etan Orgel^{1

6}, Robert J Hayashi⁷, Judith E Lieu⁸, Jennifer H Foster⁹, Matthew S Sitton¹⁰, James I Geller¹¹, Daniel I Choo¹², Arun Rangaswami¹³, Kay W Chang¹⁴, Brian Greffe¹⁵, Kenny Chan¹⁶, Alice Lee¹⁷, Eli Grunstein¹⁸, Allison F O'Neill¹⁹, Reza Rahbar²⁰, Jeffery J Anderson²¹

Affiliations

¹ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
² Departments of Pediatrics, Medicine, and Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
³ Cancer and Blood Disorders Program, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
⁴ Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, Washington, USA.
⁵ Department of Otolaryngology, Children's Hospital Los Angeles, Los Angeles, California, USA.
⁶ Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷ Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁹ Pediatric Hematology/Oncology, Texas Children's Hospital, Houston, Texas, USA.
¹⁰ Department of Otolaryngology, Texas Children's Hospital, Houston, Texas, USA.
¹¹ Division of Pediatric Oncology, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA.
¹² Department of Otolaryngology, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA.
¹³ Division of Pediatric Oncology, University of California San Francisco, San Francisco, California, USA.
¹⁴ Department of Otolaryngology, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California, USA.
¹⁵ Division of Pediatric Oncology, Colorado Children's Hospital, University of Colorado, Denver, Colorado, USA.
¹⁶ Department of Otolaryngology, Colorado Children's Hospital, University of Colorado, Denver, Colorado, USA.
¹⁷ Division of Pediatric Hematology/Oncology, Morgan Stanley Children's Hospital, New York, New York, USA.
¹⁸ Department of Otolaryngology, Morgan Stanley Children's Hospital, New York, New York, USA.
¹⁹ Division of Pediatric Oncology, Dana-Farber and Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
²⁰ Department of Otolaryngology, Boston Children's Hospital, Boston, Massachusetts, USA.
²¹ Otonomy, Inc., San Diego, California, USA.

PMID: 40128126
DOI: 10.1002/pbc.31680

Clinical Trial

Feasibility and Safety of Intratympanic Administration of Sustained-Exposure Dexamethasone Thermosensitive Gel (OTO-104) for Prevention of Cisplatin-Induced Hearing Loss in Children: A Multisite Phase 2 Randomized Clinical Trial

David R Freyer et al. Pediatr Blood Cancer. 2025 Jun.

. 2025 Jun;72(6):e31680.

doi: 10.1002/pbc.31680. Epub 2025 Mar 24.

Authors

Affiliations

¹ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
² Departments of Pediatrics, Medicine, and Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
³ Cancer and Blood Disorders Program, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
⁴ Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, Washington, USA.
⁵ Department of Otolaryngology, Children's Hospital Los Angeles, Los Angeles, California, USA.
⁶ Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷ Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁹ Pediatric Hematology/Oncology, Texas Children's Hospital, Houston, Texas, USA.
¹⁰ Department of Otolaryngology, Texas Children's Hospital, Houston, Texas, USA.
¹¹ Division of Pediatric Oncology, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA.
¹² Department of Otolaryngology, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA.
¹³ Division of Pediatric Oncology, University of California San Francisco, San Francisco, California, USA.
¹⁴ Department of Otolaryngology, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California, USA.
¹⁵ Division of Pediatric Oncology, Colorado Children's Hospital, University of Colorado, Denver, Colorado, USA.
¹⁶ Department of Otolaryngology, Colorado Children's Hospital, University of Colorado, Denver, Colorado, USA.
¹⁷ Division of Pediatric Hematology/Oncology, Morgan Stanley Children's Hospital, New York, New York, USA.
¹⁸ Department of Otolaryngology, Morgan Stanley Children's Hospital, New York, New York, USA.
¹⁹ Division of Pediatric Oncology, Dana-Farber and Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
²⁰ Department of Otolaryngology, Boston Children's Hospital, Boston, Massachusetts, USA.
²¹ Otonomy, Inc., San Diego, California, USA.

PMID: 40128126
DOI: 10.1002/pbc.31680

Abstract

Background: Cisplatin-induced hearing loss (CIHL) remains a significant complication of pediatric cancer treatment. We evaluated the feasibility, safety, and trends of the efficacy of intratympanic injections of sustained-exposure dexamethasone thermosensitive gel (OTO-104) for otoprotection.

Procedure: In this multisite randomized phase 2 trial (NCT02997189), patients aged 0.5-21 years with newly diagnosed cancer treated with cisplatin were eligible. Participants' ears were randomized to receive up to three intratympanic injections of 0.2 mL OTO-104 in one ear and no treatment contralaterally. OTO-104 was administered by an otolaryngologist within 72 hours preceding each cisplatin cycle. Feasibility was determined by the successful administration of intended doses. Treatment-emergent adverse events (TEAEs) and outcomes were monitored by physical examination, concurrent medications, otoscopy, tympanometry, and audiometry.

Results: From January 6 to September 26, 2017, 18 doses of OTO-104 were administered to 11 evaluable participants across 5 centers (range, 1-14 years; 9 neuroblastoma and 2 osteosarcoma) via intratympanic injection (9) or tympanostomy tube (2). Sixteen injections were paired with other procedural sedations and two were performed awake; all injections were successfully delivered. The median interval between OTO-104 and cisplatin was 14 hours (range, 7-64). Clinically insignificant tympanic scabs were noted in five participants; no middle ear changes were observed. There were three otologic TEAEs (two transient mild-moderate otalgia [related] and one hypoacusis [unrelated]) and no related non-otologic TEAEs. CIHL developed similarly in treated versus untreated ears; the trial was terminated early.

Conclusions: Although dexamethasone at this dose was not otoprotective, these results suggest that intratympanic injection may be safe, feasible, and a viable delivery platform for testing other otoprotectants.

Keywords: otoprotectant; ototoxicity; pediatric cancer; thermosensitive gel; tympanic injection.

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References

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1. A. J. M. Meijer, K. H. Li, B. Brooks, et al., “The Cumulative Incidence of Cisplatin‐Induced Hearing Loss in Young Children Is Higher and Develops at an Early Stage During Therapy Compared With Older Children Based on 2052 Audiological Assessments,” Cancer 128, no. 1 (2022): 169–179, https://doi.org/10.1002/cncr.33848.
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Feasibility and Safety of Intratympanic Administration of Sustained-Exposure Dexamethasone Thermosensitive Gel (OTO-104) for Prevention of Cisplatin-Induced Hearing Loss in Children: A Multisite Phase 2 Randomized Clinical Trial

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Feasibility and Safety of Intratympanic Administration of Sustained-Exposure Dexamethasone Thermosensitive Gel (OTO-104) for Prevention of Cisplatin-Induced Hearing Loss in Children: A Multisite Phase 2 Randomized Clinical Trial

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