FDA Issues Complete Response Letter for Pedmark for Prevention of Cisplatin-Induced Ototoxicity in Solid Tumors


The FDA has issued a complete response letter to Fennec Pharmaceuticals regarding its new drug application for a unique formulation of sodium thiosulfate (Pedmark) for the prevention of cisplatin-induced ototoxicity in patients from 1 month to less than 18 years of age with localized, nonmetastatic, solid tumors.

The FDA has issued a complete response letter (CRL) to Fennec Pharmaceuticals regarding its new drug application (NDA) for a unique formulation of sodium thiosulfate (Pedmark) for the prevention of cisplatin-induced ototoxicity in patients from 1 month to less than 18 years of age with localized, nonmetastatic, solid tumors.1

Following the completion of a pre-approval inspection of the manufacturing facility for sodium thiosulfate, the FDA detected deficiencies that resulted in a Form 483, according to the CRL. The Form 483 is a list of conditions or practices that need to be addressed prior to the approval of the agent, according to Fennec Pharmaceuticals, the drug developer.

There are plans to request a Type A meeting to review the issues and other matters that were included in the CRL pertaining to the actions needed for the resubmission of the NDA for the drug. Notably, no clinical efficacy or safety issues were noted during the review and the regulatory agency does not require further clinical information, according to the speciality pharmaceutical company.

“We are steadfast in our commitment to reducing the risk of life-long hearing loss for children receiving cisplatin chemotherapy who currently have no approved therapies for this devastating condition,”  Rosty Raykov, chief executive officer of Fennec, stated in a press release. “We will work closely with our manufacturer and the FDA to fully address the issues raised in the letter as expeditiously as possible.”

Sodium thiosulfate is a water-soluble thiol compound that also acts as a chemical reducing drug, according to Fennec Pharmaceuticals, the drug developer. The agent was examined in 2 phase 3 trials: The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6.

The COG Study ACCL0431 included patients who had previously been diagnosed with childhood cancers. The goal of the trial was to assess the efficacy of sodium thiosulfate in preventing hearing loss in children who were receiving cisplatin chemotherapy. Investigators hypothesized that treatment with the agent would lead to a 50% relative reduction in hearing loss in these patients.2

In the trial, investigators also set out to compare the change in mean hearing thresholds and the incidence of other grade 3/4 toxicities, as well as to monitor event-free survival (EFS) and overall survival (OS) in both patient groups.

Of 125 eligible patients, 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other cancers that were not specifically defined. Of the 125 patients enrolled, 104 were determined to be evaluable for the primary end point analysis; the majority of these patients were male (n = 64) and 29 were under 5 years of age.

For the trial, patients were randomized to receive either intravenous sodium thiosulfate at a dose of 16 g/m2 over the course of 15 minutes, 6 hours following each dose of cisplatin, or placebo. Investigators measured hearing with standard audiometry for age; these data underwent central review in accordance with the American Speech-Language-Hearing Association criteria.

Results showed that the proportion of hearing loss for those who received sodium thiosulfate arm was 28.6% versus 56.4% of those who were given the control (P = .004). Furthermore, in a subgroup of 29 patients who were less 5 years of age, the rate of hearing loss was 21.4% in the sodium thiosulfate arm versus 73.3% in the control arm (P = .005).

In the SIOPEL 6 trial, which was conducted by the International Childhood Liver Tumour Strategy Group, investigators examined the efficacy of sodium thiosulfate in reducing cisplatin-induced hearing impairment. Another focus of the trial was to monitor any potential impact of the investigational agent on response to cisplatin as well as survival. The primary end point of the trial was absolute hearing threshold at 3.5 years of age or older per central review and through the use of pure tone audiometry graded by Brock criteria.

In the trial, patients with newly diagnosed, standard-risk hepatoblastoma received 4 courses of chemotherapy bi-weekly before surgery, and 2 courses of chemotherapy after surgery. Patients were randomized to receive either cisplatin followed by sodium thiosulfate or cisplatin alone. Cisplatin was administered intravenously over the course of 6 hours at a dose of 10 mg/m2, while sodium thiosulfate was also delivered intravenously every 6 hours once treatment with cisplatin was stopped; the agent was administered over the course of 15 minutes at a dose of 20 g/m2.

In this trial, a total of 109 patients underwent randomization; 57 were enrolled to the investigational arm and 52 were assigned to the control arm. At 52 months of follow-up, the 3-year EFS rates in the cisplatin/sodium thiosulfate and cisplatin-alone arms were 82.1% and 78.8%, respectively. Moreover, the 3-year OS rates were 98.2% and 92.3% in the investigational and control arms, respectively.

Treatment failure was determined to be equivalent in both arms; this was defined as progressive disease at 4 cycles of treatment. Of 101 evaluable patients, more than half, or 63%, experienced hearing loss in the cisplatin-alone arm versus almost half of that, or 32%, in the cisplatin/sodium thiosulfate arm; this translated to a relative risk of 0.56 (P = .002). Moreover, with regard to safety, the combination of cisplatin and sodium thiosulfate was found to be well tolerated.

The marketing authorization application for the agent is currently being evaluated by the European Medicines Agency. In March 2018, sodium thiosulfate was granted a breakthrough therapy designation from the FDA; the agent was also granted fast track status.


  1. 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 August 11, 2020. https://bit.ly/30LptDZ.
  2. Clinical trials. Fennec Pharmaceuticals Inc website. Accessed August 7, 2020. https://bit.ly/30FpoSp.
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