The FDA has accepted the resubmission of an NDA for Pedmark in pediatric patients under the age of 18 with localized, non-metastatic, solid tumors.
The FDA has accepted a resubmitted new drug application (NDA) for Pedmark, a sodium thiosulfate formulation, for the prevention of platinum-induced ototoxicity in pediatric patients under the age of 18 with localized, non-metastatic, solid tumors, according to Fennec Pharmaceuticals Inc.1
Both breakthrough therapy and fast track designations were granted for Pedmark by the FDA in March 2018. Then,in August 2020, the FDA issued a complete response letter (CRL) to Fennec Pharmaceuticals Inc., following the first NDA submission for Pedmark, which noted deficiencies seen during the pre-approval inspection of the manufacturing facility. This resulted in a Form 483, which included a list of conditions and practices that would need to be addressed before the agent was to be approved.
“We are pleased that the FDA has accepted our resubmission and we look forward to working with the Agency to facilitate their review of our NDA. If approved, PEDMARK has the potential to become a transformative treatment for pediatric patients at risk of cisplatin-induced ototoxicity,” said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, in a statement.
The NDA for Pedmark was resubmitted in June 2021 and was based on the results of 2 completed phase 3 clinical trials; ACCL0431 (NCT00716976) and SIOPEL 6 (NCT00652132).
The COG ACCL0431, a randomized, open-label study, enrolled 125 patients with newly diagnosed solid tumors.2 Of those patients, 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other unspecified cancers. Additionally, 104 patients were evaluable for the primary end point of the analysis, incidence of hearing loss 4 weeks after the final cisplatin dose.
Enrollment was open to those planning to receive a chemotherapy treatment regimen that includes a cumulative cisplatin dose ≥ 200 mg/m² with individual cisplatin doses to be infused over ≤ 6 hours, and to those enrolled within the hearing assessment clinical trial, COG-ACCL05C1 (NCT00458887). Most of the participants were male (64%), and a total of 29 patients were under the age of 5 years.
Other disease characteristics include a Karnofsky and Lansky performance status of 50-100%, no prior platinum-based chemotherapy, prior cranial radiotherapy, at least 6 months since prior hematopoietic stem cell transplantation, and more.
Along with the primary end point of incidence of hearing loss 4 weeks after the final dose of cisplatin, secondary end points included change in hearing thresholds ranging from 500 hz to 8000 hz, event-free survival (EFS), overall survival (OS), and hearing loss among patients both carrying and not carrying 2 key gene mutations.
Patients were randomized and received either intravenous (IV) administration of sodium thiosulfate at a dose of 16 mg/m2 over a duration of 15 minutes, 6 hours following each dose of cisplatin, or placebo. Hearing was measured by investigators by using the standard audiometry for age before being centrally reviewed in accordance with the American Speech-Language-Hearing Association criteria.
Findings showed that 14 patients (28.6%; 95% CI, 16.6%-43.4%) had hearing loss after treatment with cisplatin in the sodium thiosulfate arm vs 31 patients (56.4%; 95% CI, 42.3%-69.7%) in the control arm (P = .00022). Patients who received sodium thiosulfate compared to those in observation were overall less likely to have hearing loss following cisplatin (odds ratio [OR], 0.31; 95% CI, 0.13-0.73; P = .0036).
A post hoc analysis, which examined 67 patients evaluable for the primary end point, revealed 28% of patients to have hearing loss in the sodium thiosulfate group vs 54% in the control group (P = .0015).
In regard to safety, 77% of patients in the sodium thiosulfate arm showed signs of hematologic toxicity compared with 77% in the control arm (P = .95). The most common grade 3/4 hematological adverse event (AEs) in the experimental vs in the control arm was neutropenia (66% vs 65%, respectively), and the most common non-hematological AE was hypokalemia shown in 17% of patients who received sodium thiosulfate vs 12% of those who received observation alone.
SIOPEL 6, a multicenter, open-label, randomized phase 3 trial, evaluated the efficacy of cisplatin plus sodium thiosulfate compared with cisplatin alone in 109 children. Investigators then looked at the primary end point of absolute hearing loss threshold and the secondary end points of response to preoperative chemotherapy, complete resection, complete remission, EFS, OS, safety, long-term renal clearance or glomerular filtration rate, and the feasibility of central audiologic review.3
Those enrolled within the study who received cisplatin were dosed at 80 mg/m2 of the body-surface area administered over a 6-hour period. Sodium thiosulfate was given at a dose of 20 mg/m2 and administered intravenously over a 15-minute period, about 6 hours after the end of cisplatin treatment.
Findings revealed that grade 1 or higher hearing loss was observed in 33% of patients in the cisplatin plus sodium thiosulfate arm vs in 63% in the cisplatin-only arm, indicating a 48% reduction in the risk of hearing loss within the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% CI, 0.33-0.81; P = .002).
The 3-year OS rate at a median follow-up of 52 months was 98% (95% CI, 88%-100%) when given the combination of cisplatin and sodium thiosulfate arm vs 92% (95% CI, 81%-97%) in the cisplatin-only arm. Additionally, the 3-year EFS rates in the cisplatin plus sodium thiosulfate arm was 82% (95% CI, 69%-90%) vs 79% (95% CI, 65%-88%) in the cisplatin-only arm.
AEs occurred in 57 patients in the combination arm compared to 52 in the monotherapy arm with the most common AEs consisting of grade 3 infection, occurring in 31% of the chemotherapy arm versus 23% of the cisplatin plus sodium thiosulfate arm, and grade 3 febrile neutropenia, which occurred in 19% versus 14%, respectively.