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.

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

In the U.S., it is estimated that over 2,000 children receive platinum based chemotherapy for localized cancers and globally approximately 7,000.  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.

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

Currently STS is being 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 is enrolling only hepatoblastoma patients.

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Sodium thiosulfate, or STS, has been shown to protect against cisplatin-induced hearing loss in animal and human studies.

Mechanism of Action

When STS 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 STS 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. STS inactivates the residual activity of these metabolites in the plasma, neutralizing their ability to cause hearing loss.

Clinical Trials

Currently STS is being 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.  Preliminary efficacy results from SIOPEL6 were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Preliminary efficacy results indicate that it is safe to treat standard risk hepatoblastoma with six cycles of Cisplatin monotherapy with the addition of the chemoprotectant STS. Preliminary efficacy results from the completed COG ACCL0431 study in 126 children and safety results from the ongoing SIOPEL 6 study in 80 patients were most recently presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 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.  Patient recruitment has now been completed and the efficacy outcome based on audiometric results will be 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 is 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.

Interim Safety Results

The Independent Data Monitoring Committee (IDMC) reviewed the efficacy results of the trial after 20, 40, 60, 80 and 100 patients to assess and rule out any potential concern of an adverse effect of STS on the efficacy of the cisplatin chemotherapy.  In February 2015, the IDMC recommended the continuation of SIOPEL 6 after conducting their final safety review on 100 patients. Previously, the IDMC reached a similar conclusion after reviewing the safety of 20, 40, 60 and 80 patients and their current recommendation on 100 patients to continue the clinical trial represents the last and final safety review.

SIOPEL6 -2 Year Interim Results of Clinical Efficacy-ASCO 2016

Newly diagnosed patients with standard risk hepatoblastoma were treated with weekly cycles of Cisplatin every two weeks, including 4 chemotherapy courses before primary tumor resection and 2 courses after surgery. Patients were randomized to Cisplatin alone or Cisplatin and STS.  Cisplatin of 80 mg/m2 was administered i.v. over 6 hours. STS was administered i.v. exactly 6 hours after stop of Cisplatin over 15 minutes at 20 g/m2. Tumor response was assessed after 2 and 4 cycles pre-operative with serum AFP and liver imaging.  In case of progression after 2 cycles, STS was stopped and doxorubicin 60 mg/m2 continuous infusion over 48 hours added.  The primary endpoint is centrally reviewed absolute hearing threshold, at the age of ≥ 3.5 years, by pure tone audiometry. The trial has 80% power to detect a reduction in hearing loss defined as Brock grade ≥ 1 from 60% of patients with Cisplatin to 35% with Cisplatin plus STS.

The efficacy results indicate the following: i) that it is safe to deliver Sodium Thiosulfate for otoprotection in Standard Risk Hepatoblastoma treated according to the SIOPEL 6 regimen; ii) there is no evidence of tumor protection and iii) the interim results of the first 68 patients achieving centrally reviewed pure tone audiometry at or above 3.5 years of age were encouraging.  Efficacy results at the end treatment for the 109 evaluable patients (52 Cisplatin, 57 Cisplatin plus STS) were complete response/partial response/progressive disease for Cisplatin: 85%/8%/5% and for Cisplatin plus STS: 91%/9%/0%.

RESULTS

109 patients (52 Cis and 57 Cis+STS) were recruited at trial closure in December 2014.
The combination of Cis+STS was generally well tolerated.
The median follow up is 34 months and provisional 2 yr EFS is Cis 86.3% and Cis+STS 89.0%; 2 yr OS is Cis 91.4% and Cis+STS 97.7%.
Treatment failure defined as PD at 4 cycles was equivalent in both arms (5 Cis; 5 Cis+STS).
Status at last follow-up (February 2016), 5 patients had died (4 Cis; 1 Cis+STS).

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

Preliminary 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) and EFS/OS (log-rank test, 2-year cumulative estimates and Cox proportional hazards model) were compared between the two groups.

        • The proportion of hearing loss for STS vs. Control was 28.6% (14/49) vs. 56.4% (31/55), respectively (p=0.004).
        • Including all 126 subjects at median post-enrollment follow-up of 2.9 years for censored patients, EFS for STS vs. Control was 61.2% vs. 69.9% (p=0.31); OS was 77.0% vs. 88.9% (p=0.029).

A subset analysis by extent of disease determined post hoc was performed:

        • For subjects with localized disease, EFS for STS (N=40) vs. Control (N=38) was 72.5% vs. 68.3% (p=0.94); HR (hazard ratio) 1.03 (p=0.94); OS was 89.0% vs. 89.5% (p=0.48); HR 1.58 (p=0.48).
        • For those with disseminated (metastatic) disease, EFS for STS (N=21) vs. Control (N=26) was 41.6% vs. 72.5% (p=0.085); HR 2.13 (p=0.092); OS was 55.9% vs. 88.1% (p=0.011); HR 3.97 (p=0.019).

Preliminary Conclusions

        • STS protects against cisplatin-induced hearing loss in children, especially for those < 5 years old.
        • In this study, use of STS did not result in lower EFS/OS in patients with localized disease. However, the lower survival among those with disseminated disease raises the concern of a tumor protective effect when STS is administered on this dose and schedule.

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 STS 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.