Sodium Thiosulfate Receives Recommendation for European Approval for Cisplatin-Induced Ototoxicity in Pediatric Patients

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion and recommended the approval of sodium thiosulfate injection (Pedmarqsi) for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to less than 18 years of age with localized, nonmetastatic solid tumors.¹

The recommendation is supported by data from the phase 3 SIOPEL 6 (NCT00652132) and COG ACCL0431 (NCT00716976) trials. In SIOPEL 6, 35.1% of pediatric patients with hepatoblastoma treated with sodium thiosulfate experienced cisplatin-induced hearing loss, compared with 67.3% of patients administered cisplatin alone. (P = .001). In COG ACCL0431, the rates of hearing loss were 28.6% and 56.4% in the sodium thiosulfate and control arms, respectively (P = .004).

The CHMP’s recommendation will be reviewed by the European Commission, and ratification of the CHMP recommendation is expected by early June 2023.

“Children treated with cisplatin for solid tumors carry a very high risk of losing their hearing permanently,” Penelope “Peppy” R. Brock, MD, PhD, of Great Ormond Street Hospital in London and International Chair of the SIOPEL 6 trial, stated in a news release. “As cure rates increase into the high nineties for several cancers, the need to resolve these permanently disabling [adverse] effects [AEs] becomes more and more pressing. I am delighted that finally we have something to offer to counter this life impacting side effect and can give children the opportunity to live healthy, happy and fully integrated lives after overcoming cancer."

In September 2022, the 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.² The regulatory decision was also supported by findings from the SIOPEL 6 and COG ACCL0431 trials.

SIOPEL 6 enrolled pediatric patients who were more than 1 month and no more than 18 years of age with standard risk hepatoblastoma.³ Patients were randomly assigned to receive neoadjuvant cisplatin with or without sodium thiosulphate. Those in the experimental arm were given intravenous sodium thiosulphate over 15 minutes beginning 6 hours after the administration of cisplatin. Patients in both arms received neoadjuvant cisplatin every 2 weeks for 4 courses, and those without evidence of disease progression proceeded to surgery. Within 3 weeks following surgery, cisplatin was given every 2 weeks for 2 courses or until disease progression or unacceptable toxicity.

The rate of Brock grade 1 or higher hearing loss was the primary end point. Secondary end points included response to preoperative chemotherapy, complete resection, complete remission, event-free survival (EFS), overall survival (OS), and safety.

Investigators of COG ACCL0431 enrolled newly diagnosed pediatric patients aged 1 year to 18 years with germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancies.⁴

Patients were randomly assigned to receive cisplatin-based chemotherapy with or without sodium thiosulfate, which was administered for 15 minutes 6 hours after the completion of each dose of cisplatin in experimental arm.

The primary end point was the incidence of hearing loss. Secondary end points consisted of change in hearing thresholds, EFS, OS, and hearing loss among patients with or without TPMT and COMT mutations.

Regarding safety, the most common AEs reported in SIOPEL 6 that occurred in at least 25% of patients with a difference of more than 5% compared with cisplatin alone included vomiting, infection, nausea, decreased hemoglobin, and hypernatremia.1 The most common AE in COG ACCL0431 was hypokalemia.

“There are currently no approved treatments in Europe to mitigate the risk of permanent and irreversible bilateral hearing loss which occurs in approximately 60 percent of children treated with cisplatin and can be as high as 90 percent,” Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, stated in a news release. “The CHMP positive opinion brings European patients and their families closer to having a preventive treatment option to prevent the devastating consequences of hearing loss following the use of cisplatin chemotherapy, an indispensable treatment of choice in many pediatric cancer cases. With approximately five thousand children eligible for treatment with a platinum-based chemotherapy each year in Europe, we are excited by the potential this therapy can offer to the pediatric oncology community.”

References

1. Fennec Pharmaceuticals receives positive CHMP opinion for Pedmarqsi™ (sodium thiosulfate) to reduce the risk of hearing loss in pediatric oncology patients. News release. Fennec Pharmaceuticals. March 31, 2023. Accessed April 3, 2023. https://investors.fennecpharma.com/news-releases/
2. FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic solid tumors. News release. FDA. September 20, 2022. Accessed April 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Cisplatin with or without sodium thiosulfate in treating young patients with stage I, II, or III childhood liver cancer (SIOPEL6). ClinicalTrials.gov. Updated May 29, 2018. Accessed April 3, 2023. https://clinicaltrials.gov/ct2/show/NCT00652132
4. Sodium thiosulfate in preventing hearing loss in young patients receiving cisplatin for newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy. ClinicalTrials.gov. Updated July 6, 2021. Accessed April 3, 2023. https://clinicaltrials.gov/ct2/show/NCT00716976