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

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

The efficacy of the product was examined in pediatric patients who were undergoing cisplatin-based chemotherapy treatment for their cancer and who were included in the following 2 randomized, open-label, multicenter 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 full response letter (CRL) to Fennec Pharmaceuticals, the drug’s developer, after a pre-approval inspection of the sodium thiosulfate manufacturing facility 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 receiving the final minutes of a type A meeting with the FDA, the NDA for Pedmark has been resubmitted regulation in June 2021.4 The the application has been accepted by the FDA later that month for filing.5 However, in November 2021, a second CRL was issued to the company after manufacturing defects were further identified.6 In April 2022, the FDA accepted new NDA submission for filingand the target action date has been set for September 23, 2022.seven

SIOPEL 6

The multicenter, randomized, controlled, open-label, Phase 3 SIOPEL 6 trial recruited 114 patients aged 1 month to 18 years who were receiving 6 cycles of perioperative cisplatin-based chemotherapy for standard-risk hepatoblastoma.8

Study participants were randomized 1:1 to receive cisplatin-based chemotherapy with (n=61) or without (n=53) sodium thiosulfate, which was dosed by body weight and administered intravenously over 15 minutes beginning 6 hours after the 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/m215gsm2and 20 gsm2respectively.

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

Of the patients who were randomized, the median age was 1.1 years (range 1.2 months to 8.2 years) and 55% were male. Additionally, 60% of patients were white, 11% were Asian, and 1.8% were black or African American.

The data showed that the incidence of hearing loss was lower in people who received sodium thiosulfate and cisplatin compared to cisplatin alone, at 39% and 68%, respectively (unadjusted relative risk of 0.58 95% CI, 0.40-0.83).

COG ACCL0431

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

Here, study participants were randomized in a 1:1 fashion to receive cisplatin-based chemotherapy with (n=61) or without (n=64) sodium thiosulfate. Cisplatin was administered according to the disease-specific treatment protocols of each trial site. Participants received sodium thiosulfate starting 6 hours after the end of each cisplatin infusion, at a dose bioequivalent to the recommended dose. The infusion with the product had to be completed at least 10 hours after the next cisplatin infusion if the treatment protocol called for several daily doses of cisplatin.

Patients were stratified by whether they had previously received cranial radiotherapy (yes vs. no). In those without prior cranial radiation therapy, randomization was stratified by age (

The primary outcome of the trial was hearing loss according to American Speech-Language-Hearing Association criteria, which was assessed at baseline and 4 weeks after the last course of cisplatin.

Efficacy was examined in a subset of 77 patients who had localized non-metastatic solid tumours, which constituted the intent-to-treat population. The median age of 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 teratoid/ atypical rhabdoid, 1.3% had choroid plexus carcinoma, and 1.3% had anaplastic astrocytoma. Seven percent of patients have already received radiotherapy.

The results indicated that the incidence of hearing loss was lower in the sodium thiosulfate/cisplatin arm compared to the cisplatin alone arm, at 44% and 58%, respectively (unadjusted relative risk, 0.75; 95%, 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. The FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized non-metastatic solid tumors. Press release. FDA. September 20, 2022. Accessed September 20, 2022. https://bit.ly/3BXm47E
  2. Fennec Pharmaceuticals Announces Acceptance of FDA Filing and Priority Review of New Drug Application for Pedmark. Press release. Fennec Pharmaceuticals. April 13, 2020. Accessed September 20, 2022. https://bit.ly/2Du9Urm
  3. Fennec Pharmaceuticals receives a complete response letter from the FDA for its new drug application for Pedmark to prevent cisplatin-associated ototoxicity in pediatric patients with localized, non-metastatic solid tumors. Press release. Fennec Pharmaceuticals. August 11, 2020. Accessed September 20, 2022. https://bit.ly/30LptDZ
  4. Fennec Pharmaceuticals is resubmitting a New Drug Application to the United States Food and Drug Administration for Pedmark. Press 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 Submission for Pedmark. Press release. Fennec Pharmaceuticals, Inc. June 22, 2021. Accessed September 20, 2022. https://bit.ly/3j4WsMX
  6. Fennec Pharmaceuticals receives a complete response letter from the FDA for its new drug application for Pedmark to prevent cisplatin-associated ototoxicity in pediatric patients with localized, non-metastatic solid tumors. Press release. Fennec Pharmaceuticals. November 30, 2021. Accessed September 20, 2022. https://bit.ly/3izYcwq
  7. Fennec Pharmaceuticals announces the FDA’s acceptance of a new drug application submission for Pedmark. Press 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