Fennec Announces Publication of Pedmark(TM) Siopel 6 Clinical Data in the New England Journal of Medicine
- SIOPEL 6 met primary endpoint (p=0.002)
- 48% reduction in the incidence of hearing loss
- No evidence of tumor protection
The NEJM publication provides the final results from the SIOPEL 6 study, a multi-centre open label randomized phase 3 study evaluating the efficacy of STS in reducing ototoxicity in patients receiving cisplatin monotherapy for standard risk hepatoblastoma. It includes hearing assessments in 101 patients and 52 month median follow up of 3 year event-free survival and 3 year overall survival data.
"I am thrilled that after 30 years of research we have found a drug which prevents the horrible life-long hearing loss which children receiving cisplatin chemotherapy pay as the price for cure of their cancer,” said
"It is exciting to see the NEJM share the positive impact and importance of PEDMARKTM in pediatric cancer with the broader clinical and research communities," said
Overview of Data Published in NEJM
The SIOPEL 6 study met its primary endpoint. Sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, reduced the incidence of cisplatin-induced hearing loss in children with standard-risk hepatoblastoma without jeopardizing overall or event-free survival.
The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin–sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin–sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin–sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.
Safety and Tolerability
In the study, the results presented showed that treatment was well tolerated and acute toxicity similar and expected between arms. The table below presents the numbers of children with adverse events of grade 3 or 4:
|Children with Grade 3 or 4 Adverse Events.*|
|Adverse Event and Grade||Cisplatin Alone
(N = 52)
(N = 57)
|no. of patients (%)|
|Allergy, grade 3||1 (2)||0|
|Febrile neutropenia, grade 3||10 (19)||8 (14)|
|Infection, grade 3||16 (31)||13 (23)|
|Hypomagnesemia, grade 3||1 (2)||1 (2)|
|Hypernatremia, grade 3||0||1 (2)|
|Vomiting, grade 3||2 (4)||4 (7)|
|Nausea, grade 3||3 (6)||2 (4)|
|Left ventricular systolic dysfunction, grade 3 or 4||0||0|
|Renal event, grade 3 or 4||0||0|
|Grade 3||8 (15)||10 (18)|
|Grade 4||0||1 (2)|
|Leukopenia, grade 3||2 (4)||2 (4)|
|Grade 3||3 (6)||7 (12)|
|Grade 4||3 (6)||3 (5)|
|Grade 3||1 (2)||1 (2)|
|Grade 4||1 (2)||1 (2)|
|Gastrointestinal event||2 (4)||3 (5)|
|Elevated liver-enzyme level|
|Grade 3||6 (12)||3 (5)|
|Grade 4||0||1 (2)|
|Elevated serum glucose level, grade 3||2 (4)||1 (2)|
|Hypermagnesemia, grade 3†||2 (4)||5 (9)|
|Hypophosphatemia, grade 3||0||5 (9)|
|Hyperkalemia, grade 3||2 (4)||0|
|Grade 3||0||4 (7)|
|Grade 4||0||1 (2)|
|Dyspnea, grade 3||1 (2)||0|
* If grade 4 is not shown, there was no grade 4 adverse event. This table includes adverse events that were associated with additional treatment (mostly doxorubicin) given to children in each group.
† The protocol specified the addition of magnesium to the hydration fluid administered with cisplatin therapy.
SIOPEL 6 is a multi-centre open label randomized phase 3 study evaluating the efficacy of STS in reducing ototoxicity in patients receiving cisplatin monotherapy for standard risk hepatoblastoma. From the beginning of 2007 to the end 2014, 52 sites from 12 countries enrolled 113 evaluable patients. The study is closed to recruitment and all protocol pre-specified IDMC safety reviews are now complete. The primary efficacy hearing endpoint analysis can be performed once patients have reached 3.5 years of age and an audiometry test can be carried out. The SIOPEL 6 study trial was designed with 80% power and a 5% significance level to detect an absolute 25% reduction in the rate of Brock grade ≥1 hearing loss with a chi-square test, from a 60% hearing loss in Cis alone arm to a 35% hearing loss in Cis+STS arm. The primary endpoint is the rate of Brock grade ≥ 1 hearing loss determined after the end of treatment at the age of ≥3.5 years by pure tone audiometry.
About PEDMARKTM (sodium thiosulfate/STS)
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.
Each year in the U.S. and
STS has been studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity: COG ACCL0431 and SIOPEL 6. Both studies are closed to recruitment. COG ACCL0431 enrolled one of five childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors. COG ACCL0431 final results were published in the Lancet Oncology. SIOPEL 6 final results were published in the
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Source: Fennec Pharmaceuticals Inc.