The FDA has granted priority review to the new drug application (NDA) for sodium thiosulfate (Pedmark) for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to <18 years of age with localized, non-metastatic, solid tumors, according to Fennec Pharmaceuticals, the drug’s developer.1
A prescription drug user fee act (PDUFA) target action date of August 10, 2020 was set by the FDA for the completion of the review.
"The FDA filing acceptance of our NDA and granting of priority review represents a significant milestone in the development of Pedmark and we look forward to working closely with the Agency during this review process,” Rosty Raykov, chief executive officer of Fennec, said in a press release.
Sodium thiosulfate has been studied by cooperative groups in 2 phase III clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. Both studies have already been completed.
ACCL0431 was a multicenter, randomized, open-label, phase III trial that enrolled participants at 38 participating Children’s Oncology Group hospitals in the US and Canada.2 Eligible patients were aged 1-18 years with newly diagnosed cancer and normal audiometry. The participants were randomized 1:1 to receive sodium thiosulfate or observation in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of 4.
Overall, 125 eligible patients were randomly assigned, and of those, 104 participants were assessable for the primary endpoint of hearing loss 4 weeks after final cisplatin dose (sodium thiosulfate, n = 49; control, n = 55). Hearing loss was identified in 14 (28.6%; 95% CI, 16.6-43.3) participants in the sodium thiosulfate group compared with 31 (56.4%; 42.3-69.7) in the control group (P = 0.00022). After adjusting for stratification variables, the likelihood of hearing loss was found to be significantly lower in the sodium thiosulfate group compared with the control group (OR, 0.31; 95% CI, 0.13-0.73; P = 0.0036).
The most common grade 3-4 hematological adverse events reported, regardless of attribution, were neutropenia (117 [66%] of 178 participant cycles in the sodium thiosulfate group vs 145 [65%] of 224 in the control group), whereas the most common non-hematological adverse event was hypokalemia (25 [17%] of 149 vs 22 [12%] of 187). Further, of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were considered probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count (26 episodes in 14 participants).
SIOPEL 6 was a multi-center, open-label, randomized phase III trial of the efficacy of sodium thiosulphate in reducing ototoxicity in patients receiving cisplatin monotherapy for standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter).3 In total, 109 children were randomly assigned to receive either cisplatin plus sodium thiosulfate (n = 57) or cisplatin alone (n = 52). The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. The main secondary end points were overall survival (OS) and event-free survival (EFS) at 3 years.
The absolute hearing threshold was assessed in 101 children and sodium thiosulfate was found to be associated with few high-grade toxic effects. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, compared to 29 of 46 (63%) in the cisplatin-alone group, demonstrating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% CI, 0.33-0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of EFS were 82% (95% CI, 69-90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65-88) in the cisplatin-alone group, and the 3-year rates of OS were 98% (95% CI, 88-100) and 92% (95% CI, 81-97), respectively.
Currently, there is no approved preventative agent for platinum-based therapy-induced ototoxicity, and only expensive, technically difficult and sub-optimal cochlear implants have been shown to provide some benefit. Moreover, infants and young children that suffer ototoxicity at critical stages of development generally lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.
1. Fennec Pharmaceutical Announces FDA Filing Acceptance and Priority Review of New Drug Application for PEDMARK [news release]. Research Triangle Park, NC. Published April 13, 2020. globenewswire.com/news-release/2020/04/13/2014977/0/en/Fennec-Pharmaceuticals-Announces-FDA-Filing-Acceptance-and-Priority-Review-of-New-Drug-Application-for-PEDMARK.html. Accessed April 14, 2020.
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 multicenter, randomized, controlled, open-label, phase 3 trial. The Lancet Oncology. doi:10.1016/S1470-2045(16)30625-8.
3. Brock PR, Maibach R, Childs M, et al. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. doi:10.1056/NEJMoa1801109
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