METHOD FOR REDUCING OTOTOXICITY IN PEDIATRIC PATIENTS RECEIVING PLATINUM-BASED CHEMOTHERAPY

1 . A method of reducing the risk of developing cisplatin-induced ototoxicity in a pediatric patient of about 5 years of age and under receiving one or more chemotherapeutic cycles of cisplatin to treat a localized and non-metastatic cancer, wherein the one or more chemotherapeutic cycles comprises administering to the patient:

(I) cisplatin at a dose of about 1 mg/kg to about 5 mg/kg or about 10 mg/m 2 to about 300 mg/m 2 per cycle, wherein the cisplatin is administered on between about 1 and 5 days per cycle; and

(II) sodium thiosulfate, at a dose of about 5 g/m 2 to about 25 g/m 2 given after each dose of the cisplatin, wherein the sodium thiosulfate is administered beginning about six hours after the completion of the administration of the cisplatin,

wherein the pediatric patient is at least about 50% less likely to experience ototoxicity than a pediatric patient administered cisplatin but not receiving an administration of sodium thiosulfate during one or more chemotherapeutic cycles to treat a localized non-metastatic cancer;

wherein ototoxicity is determined by one or more criteria selected from:

a) a reduction in hearing characterized by the American-Speech-Language-Hearing Association criteria as defined by:

(i) a reduction in hearing measured by a 20 dB loss at a single frequency;

(ii) a reduction in hearing measured by a 10 dB loss at two consecutive frequencies;

(iii) loss of response in three consecutive test frequencies where responses were previously obtained;

b) a reduction in bilateral high-frequency hearing characterized by the Brock Grading Scale criteria as defined by:

(i) a <40 dB hearing loss at all frequencies, which indicates a grade 0 or minimal hearing loss;

(ii) a AO dB hearing loss at 8,000 Hz only, which indicates a grade 1 or mild hearing loss;

(iii) a AO dB hearing loss at 4,000 Hz and above, which indicates a grade 2 or moderate hearing loss;

(iv) a AO dB hearing loss at 2,000 Hz and above, which indicates a grade 3 or marked hearing loss;

(v) a AO dB hearing loss at 1,000 Hz and above, which indicates a grade 4 or severe hearing loss; or

c) a reduction in hearing characterized by the International Society of Pediatric Oncology Boston Ototoxicity Scale criteria as defined by:

(i) a <20 dB hearing loss at all frequencies, which indicates a grade 0 hearing loss;

(ii) a >20 dB HL above 4,000 Hz, which indicates a grade 1 hearing loss;

(iii) a >20 dB HL at 4,000 Hz and above, which indicates a grade 2 hearing loss;

(iv) a >20 dB HL at 2,000 Hz or 3,000 Hz, which indicates a grade 3 hearing loss;

(v) a >40 dB HL at 2,000 Hz and above, which indicates a grade 1 hearing loss;

wherein the administration of sodium thiosulfate does not substantively affect relapse free survival or overall survival compared to a pediatric patient not administered sodium thiosulfate;

wherein the pediatric patient is at risk for cisplatin-induced nephrotoxicity; and,

wherein the administration of sodium thiosulfate does not lead to a significant reduction in glomerular filtration rate compared to a pediatric patient administered cisplatin but not receiving an administration of sodium thiosulfate during one or more chemotherapeutic cycles to treat a localized non-metastatic cancer.

2 . The method of claim 1 , wherein the administration of sodium thiosulfate does not lead to a reduction in glomerular filtration rate of grade 3 or higher as determined by National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events version 3.0 (CTCAE).

3 . The method of claim 1 , wherein the cancer is hepatoblastoma.

4 . The method of claim 1 , wherein the cancer is neuroblastoma.

5 . The method of claim 1 , wherein the cancer is medulloblastoma.

6 . The method of claim 1 , wherein the cancer is osteosarcoma.

7 . The method of claim 1 , wherein the cancer is a germ cell tumor.

8 . The method of claim 1 , wherein cisplatin is administered multiple days during each cycle, and wherein the patient's sodium serum concentration is less than 145 mg/L prior to administration of the cisplatin and sodium thiosulfate.

9 . The method of claim 8 , wherein cisplatin is administered to the pediatric patient on successive days of treatment 10 hours or longer after the completion of sodium thiosulfate administration the previous treatment day.

10 . The method of claim 1 , wherein the pediatric patient receives a cumulative dose of cisplatin across all chemotherapeutic treatment cycles of greater than 200 mg/m 2 .

11 . The method of claim 10 , wherein the cumulative dose of cisplatin is between 290 and 420 mg/m 2 .

12 . The method of claim 1 , wherein hearing loss is measured at a time of at least about 4 weeks following the last administration of cisplatin and sodium thiosulfate to the pediatric patient.

13 . The method of claim 1 , wherein the administration of sodium thiosulfate does not lead to a significant increase in serum creatinine compared to a similarly situated pediatric patient administered cisplatin but not administered sodium thiosulfate.