Cisplatin and other platinum compounds are essential chemotherapeutic components for many pediatric malignancies.  Unfortunately, platinum-based therapies cause ototoxicity in many patients, and are particularly harmful to the survivors of pediatric cancer.

PEDMARKTM(a unique formulation of sodium thiosulfate (STS)) is a water-soluble thiol compound and acts as a chemical reducing agent.  Delayed administration (4–8 h) of high dose PEDMARKTM (16–20 g/m²) protects against platinum-induced ototoxicity in animal models and in patients.

In the U.S., it is estimated that over 3,000 children receive platinum based chemotherapy for localized cancers and globally approximately 10,000.  Of these, 40% to 90% develop profound and irreversible ototoxicity.  The incidence of hearing loss in these children depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

PEDMARKTM has the potential to prevent chemotherapy-induced hearing loss and be the first available agent approved for this condition.

PEDMARKTM was studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. The cancers being studied in the two studies are very rare, although the burden of ototoxicity is disproportionate among affected children due to the efficacy of cisplatin in these diseases.  The COG ACCL0431 protocol enrolled one of five childhood cancers typically treated with intensive cisplatin therapy, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma.  SIOPEL 6 enrolled only hepatoblastoma patients.

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DOWNLOAD A PRESENTATION demonstrating the hearing differences for those on STS

PEDMARKTM has been shown to protect against cisplatin-induced hearing loss in animal and human studies.

Mechanism of Action

When PEDMARKTM is administered approximately 6 hours after cisplatin, it inactivates the metabolic by-products of cisplatin circulating in the plasma, which appear to be responsible for hearing loss. Because PEDMARKTM remains only in the plasma and does not distribute into the cells where cisplatin produces its anticancer effects, there appears to be no effect on the anticancer effectiveness of cisplatin. Further, the anticancer activity of cisplatin occurs during the first two hours after administration when the free (unbound) cisplatin distributes into the cancer cells. The cisplatin that remains in the plasma is either excreted or metabolically altered to effectively eliminate its anticancer (but not its toxic) properties. PEDMARKTM inactivates the residual activity of these metabolites in the plasma, neutralizing their ability to cause hearing loss.

Clinical Trials

PEDMARKTM was studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. The cancers being studied in the two studies are very rare, although the burden of ototoxicity is disproportionate among affected children due to the efficacy of cisplatin in these diseases. SIOPEL 6 enrolled only standard risk hepatoblastoma patients. The COG ACCL0431 protocol enrolled one of five childhood cancers typically treated with intensive cisplatin therapy, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma.  Final efficacy results from SIOPEL6 were presented in October 2017 at the 49th Congress of the International Society of Pediatric Oncology (SIOP 2017) in Washington, D.C.  Final results from the completed COG ACCL0431 study in 126 children was published in Lancet Oncology in December 2016. The data presented are described below.

SIOPEL 6

SIOPEL 6 study, “A Multicenter Open Label Randomized Phase III Trial of the Efficacy of Sodium Thiosulfate in Reducing Ototoxicity in Patients Receiving Cisplatin Chemotherapy for Standard Risk Hepatoblastoma,” is being conducted by The International Childhood Liver Tumour Strategy Group, SIOPEL.  The study was initiated in October 2007 and completed enrollment of  109 evaluable patients in December 2014.  Efficacy outcome based on audiometric results were evaluated on an ongoing basis as each child reaches the age of 3.5 years.

The primary objectives of the study are:

        • To assess the efficacy of STS to reduce the hearing impairment caused by cisplatin
        • To carefully monitor any potential impact of STS on response to cisplatin and survival
        • The primary endpoint of the study was centrally reviewed absolute hearing threshold, at the age of ≥3.5 yrs, by pure tone audiometry, graded by Brock criteria.

Methods

        • Newly diagnosed patients with standard risk hepatoblastoma are treated with 4 chemotherapy courses every 2 weeks before surgery and 2 courses after surgery.
        • Patients are randomly assigned to receive cisplatin alone or cisplatin followed by STS. Cisplatin 80 mg/m² is administered i.v. over 6 hrs.
        • STS is administered i.v. exactly 6 hrs after stop of cisplatin over 15 minutes at 20g/m².

RESULTS

One hundred and nine randomised patients (52 Cis and 57 Cis+STS) are evaluable. The combination of Cis+STS was generally well tolerated. With a follow up of 52months, 3yr EFS is Cis 78.8% and Cis+STS 82.1% 3yr OS is Cis 92.3% and Cis+STS 98.2%. Treatment failure defined as PD at 4 cycles was equivalent in both arms. Among the first 99 evaluable patients, hearing loss occurred in 30/45=67.0% under Cis and in 20/54=37.0% under Cis+STS, corresponding to a relative risk of 0.56(P=0.0033).

COG ACCL0431

COG Study ACCL0431, “A Randomized Phase III Study of Sodium Thiosulfate for the Prevention of Cisplatin-Induced Ototoxicity in Children,” finished enrollment of 131 patients in Q1 2012. The patients had been previously diagnosed with childhood cancers.

The primary endpoint was to evaluate the efficacy of STS for prevention of hearing loss in children receiving cisplatin chemotherapy (hypothesis: 50% relative reduction in hearing loss)

Secondary endpoints included:

        • Compare change in mean hearing thresholds
        • Compare incidence of other Grade 3/4 toxicities (renal and hematological)
        • Monitor Event Free Survival (EFS) and Overall Survival (OS) in two groups

Results

126 eligible subjects were enrolled with germ cell tumor (32), osteosarcoma (30), neuroblastoma (26), medulloblastoma (26), hepatoblastoma (7) or other (5). Of these, 104 subjects (64 male and 29 <5 years old) were evaluable for the primary endpoint.

Subjects were randomized either to no treatment (control) or treatment with STS 16 grams/m2 IV over 15 minutes 6 hours after each cisplatin dose. Hearing was measured using standard audiometry for age and data were reviewed centrally using American Speech-Language-Hearing Association criteria.

The proportion of subjects with hearing loss assessed at 4 weeks post the final cisplatin dose (primary endpoint)..

        • The proportion of hearing loss for STS vs. Control was 28.6% (14/49) vs. 56.4% (31/55), respectively (p=0.004).
        • In a predefined subgroup of patients less than 5 years old with 29 eligible subjects: STS vs. Control was 21.4% (3/14) vs. 73.3% (11/15), respectively (p=0.005)

overall hearing data

COG ACCL0431 – CONCLUSIONS

        • STS protects against cisplatin-induced hearing loss in children, especially for those < 5 years old.

Further research including the final results of SIOPEL 6 study is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies.

The Opportunity

Currently, there are no commercially available drugs to prevent cisplatin-induced hearing loss.

Fennec Pharma has received Orphan Drug Designation in the U.S. for the use of PEDMARKTM in the prevention of platinum-induced ototoxicity in pediatric patients, providing seven and a half years of market exclusivity upon regulatory approval.

Collaborations

Fennec Pharma licensed one US and 9 foreign patents from Oregon Health and Science University for STS. The STS methods of use patents expire in Europe and Japan in 2021 and are currently pending in the US.

Publications

Brock PR, et al. J Clin Oncol 2012;20:2408-2417
Brock PR, Knight K, Freyer DR, et al. Platinum-Induced Ototoxicity in Children: A Consensus
Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol 2012;20:2408-2417

Doolittle ND, et al. Clin Cancer Res 2001;7(3):493-500.
Doolittle ND, Muldoon LL, Brummett RE, et al. Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 2001;7(3):493-500.

Gilmer Knight KR, et.al. J Clin Oncol 2005;23(34):8588-8596
Gilmer Knight, KR, Kraemer, DF, Neuwelt, EA. Ototoxicity in Children Receiving Platinum Chemotherapy: Underestimating a Commonly Occurring Toxicity That May Influence Academic and Social Development. J Clin Oncol 2005;23(34):8588-8596

Neuwelt EA, et al.,J Pharmacol Exp Ther 1998;286(1):77-84
Neuwelt EA, Brummet RE, Doolittle ND, et al. First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 1998;286(1):77-84.