FDA Approves Pedmark to Reduce Risk of Ototoxicity in Pediatric Solid Tumors

The FDA has granted approval to Pedmark to reduce the risk of ototoxicity associated with cisplatin in pediatric patients.

The FDA has approved sodium thiosulfate (Pedmark) to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic solid tumors who are aged 1 month and older.1

The product's efficacy was evaluated in pediatric patients who were undergoing treatment with cisplatin-based chemotherapy for their cancer. Patients examined were enrolled in either the multicenter, open-label, randomized controlled SIOPEL 6 (NCT00652132) or COG ACCL0431 (NCT00716976) trial.

In August 2020, the first new drug application (NDA) submission for Pedmark, a sodium thiosulfate formulation, received a priority review designation from the FDA. Only a few days later, the FDA issued a complete response letter to the drug developer, Fennec Pharmaceutical, due to the discovery of deficiencies during the pre-approval inspection of the manufacturing facility, which resulted in a Form 483.

Then in June 2021, the NDA was resubmitted to the FDA for Pedmark for the prevention of ototoxicity induced by cisplatin-based chemotherapy in patients under the age of 18 years old with localized, non-metastatic solid tumors. This application was accepted later that month by the FDA for filing.

In the randomized, open-label COG ACCL0431 study, 125 patients with newly diagnosed solid tumors were enrolled.2 Among these patients, 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other unspecified cancers. There were 104 patients evaluable for the primary end point of the analysis which was incidence of hearing loss 4 weeks after the final cisplatin dose.

Those eligible for enrollment were patients planning to receive a chemotherapy treatment regimen including a cumulative cisplatin dose ≥ 200 mg/m² with individual cisplatin doses to be infused over ≤ 6 hours. Patients must have been enrolled in the hearing assessment clinical trial, COG-ACCL05C1 (NCT00458887), have a Karnofsky and Lansky performance status of 50-100%, no prior platinum-based chemotherapy, prior cranial radiotherapy, and have been at least 6 months since prior hematopoietic stem cell transplantation.

Patients stratified depending on if they received prior cranial radiation or not. For those without prior cranial radiation, randomization was further stratified by age (<5 years vs ≥5 years) and duration of cisplatin infusion (<2 hours vs ≥2 hours).

Secondary end points of the trial included change in hearing thresholds ranging from 500 hz to 8000 hz, event-free survival (EFS), overall survival (OS), and hearing loss among patients both carrying and not carrying 2 key gene mutations.

Most participants were male (64%), and 29 patients were under the age of 5 years. Patients were randomized and received either intravenous (IV) administration of sodium thiosulfate 16 mg/m2 over a duration of 15 minutes, 6 hours following each dose of cisplatin, or placebo. Hearing was measured by investigators by using the standard audiometry for age before being centrally reviewed in accordance with the American Speech-Language-Hearing Association criteria.

Results showed that 14 patients (28.6%; 95% CI, 16.6%-43.4%) had hearing loss after treatment with cisplatin in the sodium thiosulfate arm vs 31 patients (56.4%; 95% CI, 42.3%-69.7%) in the control arm (P = .00022). Those given sodium thiosulfate were less likely to have hearing loss following cisplatin vs those in observation (odds ratio [OR], 0.31; 95% CI, 0.13-0.73; P = .0036).

A post hoc analysis examining 67 patients evaluable for the primary end point revealed 28% of patients to have hearing loss in the sodium thiosulfate group vs 54% in the control group (P = .0015).

Regarding safety, 77% of patients in the sodium thiosulfate arm showed signs of hematologic toxicity compared with 77% in the control arm (P = .95). The most common grade 3 or 4 hematological adverse event (AEs) in the experimental vs in the control arm was neutropenia (66% vs 65%, respectively). The most common non-hematological AE was hypokalemia in 17% of patients who received sodium thiosulfate vs 12% of those in the observation alone arm.

As for the multicenter, open-label, randomized phase 3 SIOPEL 6 trial, investigators aimed to evaluate the efficacy of cisplatin plus sodium thiosulfate vs cisplatin alone in 109 children.3 Patients who received cisplatin were dosed at 80 mg/m2 of the body-surface area administered over a 6-hour period. Sodium thiosulfate was given at a dose of 20 mg/m2 and administered intravenously over a 15-minute period, about 6 hours after the end of cisplatin treatment.

The primary end point was absolute hearing loss threshold with secondary end points consisting of response to preoperative chemotherapy, complete resection, complete remission, EFS, OS, safety, long-term renal clearance or glomerular filtration rate, and the feasibility of central audiologic review.

Grade 1 or higher hearing loss was seen in 33% of patients in the cisplatin plus sodium thiosulfate arm vs in 63% in the cisplatin-only arm. This resulted in a 48% reduction in the risk of hearing loss within the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% CI, 0.33-0.81; P = .002). The 3-year OS rate at a median follow-up of 52 months was 98% (95% CI, 88%-100%) with cisplatin plus sodium thiosulfate vs 92% (95% CI, 81%-97%) for cisplatin-only. In the cisplatin plus sodium thiosulfate arm, the 3-year EFS rate was 82% (95% CI, 69%-90%) vs 79% (95% CI, 65%-88%) in the cisplatin-only arm.

AEs occurred in 57 patients in the combination arm compared to 52 in the monotherapy arm with the most common AEs consisting of grade 3 infection, occurring in 31% of the chemotherapy arm versus 23% of the cisplatin plus sodium thiosulfate arm, and grade 3 febrile neutropenia, which occurred in 19% versus 14%, respectively.

  1. FDA Approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, nonmetastatic solid tumors. News release. FDA. September 20, 2022. Accessed September 21, 2022. https://bit.ly/3qX6Yc8
  2. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74. doi:10.1016/ S1470-2045(16)30625-8
  3. Brock PR, Maibahc R, Childs M, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-2385. doi:10.1056/NEJMoa1801109
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