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The FDA has granted a priority review designation to a new drug application for a unique formulation of sodium thiosulfate 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 granted a priority review designation to a 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, according to an announcement from Fennec Pharmaceuticals Inc.1
“The FDA filing acceptance of our NDA and granting of priority review represents a significant milestone in the development of Pedmark and we look forward to working closely with the Agency during this review process,” Rosty Raykov, chief executive officer of Fennec, stated in the press release.
Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by August 10, 2020.
Sodium thiosulfate is a water-soluble thiol compound that also acts as a chemical reducing drug, according to Fennec. The agent was evaluated in 2 phase 3 trials: The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6.
The COG Study ACCL0431 enrolled patients who had previously been diagnosed with childhood cancers. In the trial, investigators set out to examine the efficacy of sodium thiosulfate in preventing hearing loss in children who were receiving cisplatin; specifically, the hypothesis was that the agent would result in a 50% relative reduction in hearing loss in this population.2
Key secondary objectives included: to compare the change in mean hearing thresholds, to compare the incidence of other grade 3/4 toxicities, and to monitor event-free survival (EFS) and overall survival (OS) in both 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. Investigators determined that 104 of the 125 patients enrolled were evaluable for the primary end point analysis; 64 of these patients were male and 29 were under 5 years of age.
Patients were randomized to receive either 16 g/m2 of intravenous sodium thiosulfate over 15 minutes, 6 hours following each dose of cisplatin or placebo. Investigators measured hearing with standard audiometry for age; this information underwent central review in accordance with the American Speech-Language-Hearing Association criteria.
Results demonstrated that the proportion of hearing loss for those in the sodium thiosulfate arm was 28.6% versus 56.4% in the control arm (P = .004). Furthermore, in a subgroup of patients under 5 years of age (n = 29), the rates of hearing loss were 21.4% and 73.3% in the sodium thiosulfate and control arms, respectively (P = .005).
In the SIOPEL 6 trial, conducted by the International Childhood Liver Tumour Strategy Group, investigators evaluated the efficacy of sodium thiosulfate in reducing hearing impairment induced by treatment with cisplatin. Another focus 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 prior to surgery, and 2 courses of chemotherapy following surgery. Participants were randomized to receive either cisplatin chemotherapy followed by sodium thiosulfate or cisplatin alone. Cisplatin was given intravenously over 6 hours at a dose of 10 mg/m2, while sodium thiosulfate was also delivered intravenously every 6 hours after treatment with cisplatin was stopped; it was given over the course of 15 minutes at a dose of 20 g/m2.
A total of 109 patients underwent randomization, with 57 enrolled to the investigational arm and 52 enrolled to the control arm. At 52 months of follow-up, the 3-year EFS rate with cisplatin/sodium thiosulfate was 82.1% versus 78.8% with cisplatin alone. Moreover, the 3-year OS rates were 98.2% and 92.3% in the investigational and control arms, respectively.
Treatment failure was found to be equivalent in both arms; this was defined as disease progression at 4 cycles of treatment. Of 101 evaluable patients, 63% experienced hearing loss in the cisplatin-alone arm versus just 32% in the cisplatin/sodium thiosulfate arm; this translated to a relative risk of 0.56 (P = .002). Additionally, the combination of cisplatin and sodium thiosulfate was found to be well tolerated, overall.
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.