RESEARCH TRIANGLE PARK, N.C. — New Phase 2 clinical data from Japan found that pediatric and adolescent and young adult (AYA) patients receiving PEDMARK® (sodium thiosulfate) following cisplatin chemotherapy experienced a significantly lower rate of hearing loss compared with a prespecified historical benchmark.
Fennec Pharmaceuticals announced detailed results from the investigator-initiated STS-J01 study, which are being presented September 17 at the 58th Annual International Society of Pediatric Oncology (SIOP) Annual Meeting in San Antonio.
The study evaluated PEDMARK for reducing cisplatin-induced ototoxicity in pediatric and AYA patients with non-metastatic solid tumors in Japan.
Hearing Loss Reported in 24% of Primary Efficacy Population
The study enrolled 33 patients across 11 institutions in Japan, including 27 patients in the primary cohort and six patients in exploratory cohorts.
Among the 25 patients included in the primary efficacy population, 24% (6 of 25) developed hearing loss according to American Speech-Language-Hearing Association (ASHA) criteria, compared with a prespecified historical benchmark of 56.4%. The difference was statistically significant (P=0.001).
Nineteen of the 25 patients, or 76%, remained free of ASHA-defined hearing loss. Using Brock grading criteria, 84% had Grade 0 hearing loss, and researchers observed no Grade 3 or Grade 4 hearing loss.
STS-J01 is an open-label, single-arm trial, meaning the hearing outcomes were compared with a prespecified historical benchmark rather than a concurrent randomized control group.
Patients received PEDMARK intravenously six hours after cisplatin infusion, with dosing adjusted according to body weight.
Findings Add to Evidence on Six-Hour Administration
Objective tumor responses were reported in 23 of 24 evaluable patients (95.8%). Prospective pharmacokinetic analyses also provided additional mechanistic evidence supporting the six-hour interval between cisplatin and PEDMARK administration.
The findings add to the growing evidence supporting PEDMARK for the prevention of cisplatin-related hearing loss. Data presented earlier this year also examined hearing protection and antitumor outcomes with sodium thiosulfate, with the six-hour interval between cisplatin and PEDMARK administration playing a central role in the treatment approach.
“The clinical and pharmacologic findings of STS-J01 are compelling. We observed a significant reduction in hearing loss, with no Grade 3 or Grade 4 hearing loss by Brock criteria, alongside a 95.8% objective response rate in evaluable patients.”
— Pierre S. Sayad, PhD, M.S., Chief Medical Officer, Fennec Pharmaceuticals
Sayad said the prospective pharmacokinetic analyses provide additional insight into why the six-hour interval matters, supporting a model in which PEDMARK acts on residual circulating and exchangeable platinum after cisplatin has had time to distribute and initiate its antitumor activity.
Safety and Antitumor Activity
According to Fennec, the safety findings were consistent with PEDMARK’s known tolerability profile and the expected toxicities associated with cisplatin-containing chemotherapy. No serious adverse events were attributed to PEDMARK, and investigators reported no Grade 4 PEDMARK-related toxicity.
The STS-J01 results add to findings from the Children’s Oncology Group ACCL0431 and SIOPEL 6 studies. Fennec said STS-J01 represents a third study providing evidence that delayed PEDMARK administration did not interfere with cisplatin antitumor activity.
These results add to previously reported research examining PEDMARK for the prevention of cisplatin-related hearing loss, including findings on treatment timing and whether hearing protection can be achieved without compromising cisplatin’s antitumor activity.
Cisplatin-Related Hearing Loss
Cisplatin and other platinum-based chemotherapies are widely used in the treatment of solid tumors, but they can cause permanent and irreversible hearing loss.1 Published studies have estimated that between 60% and 90% of patients treated with cisplatin may develop some degree of hearing loss, depending on factors including the dose and duration of treatment.2
For some patients, the resulting hearing loss may require lifelong use of hearing aids or cochlear implants.3 In children and young people, treatment-related hearing loss can also have long-term consequences for speech and language development, academic performance, social-emotional development, and other aspects of life.4,5
Potential Expansion in Japan
PEDMARK is currently FDA approved in the United States to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients one month of age and older with localized, non-metastatic solid tumors. It is also recognized by the National Comprehensive Cancer Network with a Category 2A recommendation for use in adolescent and young adult patients.
Fennec said it is pursuing registration for PEDMARK in Japan and is exploring potential partnering or licensing opportunities in the country.
The Japanese study adds another dataset to a growing body of research examining prevention of cisplatin-induced hearing loss, an important long-term consideration for children and young adults undergoing cancer treatment.
About PEDMARK®
PEDMARK® (sodium thiosulfate injection) is FDA approved to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients one month of age and older with localized, non-metastatic solid tumors. PEDMARK has been studied in two randomized Phase 3 clinical trials, Children’s Oncology Group Protocol ACCL0431 and SIOPEL 6. PEDMARK is also recommended for the adolescent and young adult population by the National Comprehensive Cancer Network with a Category 2A endorsement.
About Fennec Pharmaceuticals
Fennec Pharmaceuticals Inc. is a specialty pharmaceutical company committed to addressing ototoxicity in cancer patients who receive cisplatin-based chemotherapy. Fennec is focused on the commercialization of PEDMARK® to reduce the risk of platinum-induced ototoxicity in cancer patients. PEDMARK received FDA approval in September 2022 and European Commission approval in June 2023 and United Kingdom approval in October 2023 under the brand name PEDMARQSI®.
In March 2024, Fennec entered into an exclusive licensing agreement under which Norgine Pharmaceuticals Ltd. will commercialize PEDMARQSI® in Europe, the U.K., Australia and New Zealand. PEDMARQSI is now commercially available in multiple countries.
References
1 Sheth S, et al. Mechanisms of Cisplatin Ototoxicity and Progress in Otoprotection. Frontiers in Cellular Neuroscience. 2017;11.
2 Langer T, am Zehnhoff-Dinnesen A, Radtke S, Meitert J, Zolk O. Understanding platinum-induced ototoxicity. Trends Pharmacol Sci. 2013;34(8):458-469.
3 Landier W. Ototoxicity and Cancer Therapy. Cancer. 2016;122(11):1647-1658.
4 Clemens E, van den Heuvel-Eibrink MM, Mulder RL, et al. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium. Lancet Oncol. 2019;20(1):e29-e41.
5 Bass JK, Knight KR, Yock TI, Chang KW, Cipkala D, Grewal SS. Evaluation and management of hearing loss in survivors of childhood and adolescent cancers: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2016;63(7):1152-1162.
6 Chattaraj A, et al. Cisplatin-Induced Ototoxicity: A Concise Review of the Burden, Prevention, and Interception Strategies. JCO Oncol Pract. 2023;19.
7 Freyer DR, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74.
8 Rajput K, Edwards L, Brock P, Abiodun A, Simpkin P, Al-Malky G. Ototoxicity-induced hearing loss and quality of life in survivors of paediatric cancer. Int J Pediatr Otorhinolaryngol. 2020;138:110401. doi:10.1016/j.ijporl.2020.110401.
9 Bass JK, Knight KR, Yock TI, Chang KW, Cipkala D, Grewal SS. Evaluation and management of hearing loss in survivors of childhood and adolescent cancers: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2016;63(7):1152-1162.
Source: Fennec Pharmaceuticals
