EU's CHMP Recommends Injection Against Pediatric Chemo-Induced Ototoxicity

The European Medicine Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization to sodium thiosulfate injection (Pedmarqsi) as a preventative measure against hearing loss associated with cisplatin-based chemotherapy in pediatric patients with localized, non-metastatic solid tumors, according to a press release from Fennec Pharmaceuticals.¹

"As cure rates increase into the high nineties for several cancers, the need to resolve these permanently disabling [AEs] becomes more and more pressing," according to an expert from Great Ormond Street Hospital in London.

The European Commission will review the CHMP’s recommendation and issue a decision on the injection’s approval by early June 2023.

The CHMP based its recommendation on data from the phase 3 SIOPEL6 trial (NCT00652132) and the phase 3 COG ACCL0431 study (NCT00716976), both of which compared sodium thiosulfate plus cisplatin with cisplatin alone for reducing the risk of cisplatin-induced hearing loss in pediatric patients.

In the COG ACCL0431, the hearing loss incidence rate was 28.6% in patients treated with sodium thiosulfate plus cisplatin compared with 56.4% in the cisplatin alone arm (P = .004).

In the SIOPEL6 study, the hearing loss incidence rate was 35.1% with sodium thiosulfate plus cisplatin vs 67.3% with cisplatin alone (P = .001).

“Children treated with cisplatin for solid tumors carry a very high risk of losing their hearing permanently,” international chair of the SIOPEL6 trial Penelope R. Brock, MD, PhD, of Great Ormond Street Hospital in London, said in the press release. “As cure rates increase into the high nineties for several cancers, the need to resolve these permanently disabling [AEs] becomes more and more pressing.”

Patients included in the COG ACCL0431 trial received sodium thiosulfate intravenously at a dose level of 16 g/m2 or 533 mg/kg 6 hours following each cisplatin infusion.

The primary end point of COG ACCL0431 trial was the incidence of hearing loss in pediatric patients. Secondary end points in both trials included overall survival (OS) and event-free survival (EFS).

For the COG ACCL0431 trial, patients 1 to 18 years old with a newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancies were able to enroll on the trial. Additionally, those older than 16 years of age needed to have a Karnofsky performance status of 50% to 100%, and those 16 years or younger needed to have a Lanksy performance status of 50% to 100%.

In the SIOPEL6 trial, patients were randomly assigned 1:1 to either receive cisplatin-based chemotherapy with or without sodium thiosulfate injection at several potential dose levels including 10 g/m2, 15 g/m2, 20 g/m2.

The primary end point of the SIOPEL6 trial was the incidence of hearing loss. Secondary end points included OS and EFS.

Patients older than 1 month and 18 years or younger who had standard risk hepatoblastoma were eligible for enrollment on the SIOPEL6 trial. Additional inclusion criteria included having written informed consent and the ability to comply with requirements for submission of material for central review. Patients who had hepatocellular carcinoma, abnormal renal function, recurrent disease, or received any previous chemotherapy were not eligible to enroll.

The most common toxicity in the COG ACCL0431 trial was hypokalemia.

Common adverse effects (AEs) in the SIOPEL6 study included vomiting, infection, nausea, decreased hemoglobin, and hypernatremia.

The FDA previously approved sodium thiosulfate injection in September 2022 to decrease the risk of cisplatin-associated hearing loss in pediatric patients.² Data from the SIOPEL6 trial and COG ACCL0431 study supported the FDA’s decision to approve the injection. Additionally, the FDA granted orphan drug exclusivity to the injection in this patient population in January 2023.³

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 6, 2023. bit.ly/3UcUSJI
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 6, 2023. https://bit.ly/3DLjVgC
3. Fennec Pharmaceuticals announces Pedmark® (sodium thiosulfate injection) receives orphan drug exclusivity from U.S FDA. News release. Fennec Pharmaceuticals. January 31, 2023. Accessed April 6, 2023. bit.ly/3HPPnw4