FDA Approves Pedmark for Prevention of Platinum-Induced Ototoxicity in Pediatric Solid Tumors

FDA

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

The efficacy of the product was examined in pediatric patients who were undergoing treatment with cisplatin-based chemotherapy for their cancer who were included in the following 2 multicenter, open-label, randomized controlled trials: SIOPEL 6 (NCT00652132) and COG ACCL0431 (NCT00716976).

The first new drug application (NDA) submission for the agent received a priority review designation from the FDA in August 2020.² However, a few days later, the FDA issued a complete response letter (CRL) to Fennec Pharmaceuticals, the drug developer, after a pre-approval inspection of the manufacturing facility for sodium thiosulfate revealed deficiencies that resulted in a Form 483, which detailed conditions or practices that needed to be addressed before the agent could receive approval.³

After receipt of the final minutes from a Type A meeting with the FDA, the NDA for Pedmark was resubmitted to the regulatory in June 2021.⁴ The application was accepted by the FDA later that month for filing.⁵ However, in November 2021, a second CRL was issued to the company after manufacturing deficiencies were still identified.⁶ In April 2022, the FDA accepted the NDA resubmission for filing, and the target action date was set for September 23, 2022.⁷

SIOPEL 6

The multicenter, randomized, controlled, open-label, phase 3 SIOPEL 6 trial enrolled 114 patients who were between the ages of 1 month and 18 years who were receiving 6 cycles of perioperative cisplatin-based chemotherapy for standard-risk hepatoblastoma.⁸

Study participants were randomly assigned 1:1 to receive cisplatin-based chemotherapy with (n = 61) or without (n = 53) sodium thiosulfate, which was dosed based on body weight and administered intravenously over the course of 15 minutes beginning 6 hours after completion of each cisplatin infusion. For those weighing less than 5 kg, 5 kg to 10 kg, or more than 10 kg, sodium thiosulfate was administered at 10 g/m², 15 g/m², and 20 g/m², respectively.

Stratification factors included country and age (older or younger than 15 months). The primary outcome of the trial was the percentage of patients with Brock grade 1 or higher hearing loss, which was evaluated using pure tone audiometry following study treatment or at an age of at least 3.5 years—whichever was later.

Among the patients who underwent randomization, the median age was 1.1 years (range, 1.2 months to 8.2 years), and 55% were male. Moreover, 60% of patients were White, 11% were Asian, and 1.8% were Black or African American.

Data showed that the incidence of hearing loss was lower in those who received sodium thiosulfate and cisplatin vs cisplatin alone, at 39% and 68%, respectively (unadjusted relative risk 0.58; 95% CI, 0.40-0.83).

COG ACCL0431

The multicenter, randomized, controlled, open-label phase 3 COG ACCL0431 trial included 125 patients between the ages of 1 year and 18 years who were receiving a chemotherapy regimen that included a cumulative cisplatin dose of 200 mg/m² or higher, with individual cisplatin doses to be infused over 6 hours or less.⁸

Here, study participants were randomly assigned in a 1:1 fashion to receive cisplatin-based chemotherapy with (n = 61) or without (n = 64) sodium thiosulfate. Cisplatin was given in accordance with each trial site's disease-specific treatment protocols. Participants were given sodium thiosulfate starting 6 hours following each infusion of cisplatin was completed, at a dose that was bioequivalent to the recommended dose. The infusion with the product needed to be completed at least 10 hours following the next cisplatin infusion if the treatment protocol called for several daily doses of cisplatin.

Patients were stratified based on whether they received prior cranial radiation (yes vs no). In 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).

The primary outcome for the trial was hearing loss in accordance with American Speech-Language-Hearing Association criteria, which was evaluated at baseline and 4 weeks after the final course of cisplatin.

Efficacy was examined in a subset of 77 patients who had localized, nonmetastatic solid tumors, who comprised the intention-to-treat population. The median age in these patients was 8 years (range, 1-18) and 61% were male. Sixty-two percent of patients were White, 14% were Black or African American, and 2.6% were Asian. The median Karnofsky or Lansky performance status was 90 (range, 50-100).

Twenty-seven percent of patients had an underlying diagnosis of medulloblastoma, 26% had osteosarcoma, 23% had germ cell tumor, 10% had neuroblastoma, 8% had hepatoblastoma, 2.6% had atypical teratoid/rhabdoid tumor, 1.3% had choroid plexus carcinoma, and 1.3% had anaplastic astrocytoma. Seven percent of patients previously received radiation.

Findings indicated that the incidence of hearing loss was lower in the sodium thiosulfate/cisplatin arm vs the cisplatin-alone arm, at 44% and 58%, respectively (unadjusted relative risk, 0.75;95% CI, 0.48-1.18).

Regarding safety, the most common toxicities reported in the 2 trials included vomiting, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.

References

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 20, 2022. https://bit.ly/3BXm47E
2. Fennec Pharmaceuticals announces FDA filing acceptance and priority review of new drug application for Pedmark. News release. Fennec Pharmaceuticals. April 13, 2020. Accessed September 20, 2022. https://bit.ly/2Du9Urm
3. Fennec Pharmaceuticals receives complete response letter from the FDA for its new drug application for Pedmark to prevent ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic, solid tumors. News release. Fennec Pharmaceuticals. August 11, 2020. Accessed September 20, 2022. https://bit.ly/30LptDZ
4. Fennec Pharmaceuticals resubmits new drug application to US Food and Drug Administration for Pedmark. News release. Fennec Pharmaceuticals, Inc. May 28, 2021. Accessed September 20, 2022. https://bit.ly/3pj91FO
5. Fennec Pharmaceuticals announces FDA acceptance of new drug application resubmission for Pedmark. News release. Fennec Pharmaceuticals, Inc. June 22, 2021. Accessed September 20, 2022. https://bit.ly/3j4WsMX
6. Fennec Pharmaceuticals receives complete response letter from the FDA for its new drug application for Pedmark to prevent ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic, solid tumors. News release. Fennec Pharmaceuticals. November 30, 2021. Accessed September 20, 2022. https://bit.ly/3izYcwq
7. Fennec Pharmaceuticals announces FDA acceptance for filing of new drug application resubmission for Pedmark. News release. Fennec Pharmaceuticals. April 27, 2022. Accessed September 20, 2022. https://bit.ly/37TCwJM
8. Pedmark. Prescribing information. Fennec Pharmaceuticals, Inc; 2022. Accessed September 20, 2022. https://bit.ly/3R1zd3Z