On September 20, the U.S. Food and Drug Administration (FDA) 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.
Efficacy was evaluated in two multicenter, open-label, randomized controlled trials in pediatric patients undergoing treatment with cisplatin-based chemotherapy for cancer: SIOPEL 6 (ClinicalTrials.gov identifier NCT00652132) and COG ACCL0431 (ClinicalTrials.gov identifier NCT00716976).
SIOPEL 6 and COG ACCL0431
SIOPEL 6 enrolled 114 patients with standard-risk hepatoblastoma undergoing six cycles of perioperative cisplatin-based chemotherapy. Patients were randomly assigned 1:1 to receive cisplatin-based chemotherapy with or without sodium thiosulfate administered at various doses of 10 g/m2, 15 g/m2, or 20 g/m2 based on actual body weight. The primary outcome was the percentage of patients with Brock Grade ≥ 1 hearing loss, assessed using pure tone audiometry after treatment or at an age of at least 3.5 years (whichever was later). The incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (39%) compared with the cisplatin-alone arm (68%); unadjusted relative risk 0.58 (95% confidence interval [CI] = 0.40–0.83).
COG ACCL0431 enrolled 125 pediatric patients with solid tumors undergoing a chemotherapy regimen including cumulative cisplatin doses of 200 mg/m2 or higher, with individual cisplatin doses to be infused over 6 hours or less. Patients were randomly assigned 1:1 to receive cisplatin-based chemotherapy with or without sodium thiosulfate. Efficacy was evaluated in a subset of 77 patients with localized, nonmetastatic solid tumors. The primary outcome was hearing loss according to American Speech-Language-Hearing Association criteria, assessed at baseline and 4 weeks after the final course of cisplatin. The incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (44%) compared with the cisplatin-alone arm (58%); unadjusted relative risk 0.75 (95% CI = 0.48–1.18).
The most common adverse reactions reported in the two trials (≥ 25% with difference between arms of > 5% compared to cisplatin alone) were vomiting, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.
The recommended sodium thiosulfate dose is based on surface area according to actual body weight. Sodium thiosulfate is administered as an intravenous infusion over 15 minutes following cisplatin infusions that are 1 to 6 hours in duration.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The application also was granted Orphan Drug designation.