Method for reducing ototoxicity in pediatric patients receiving platinum-based chemotherapy

(Proposed amendment):

• A method of reducing ototoxicity in a pediatric patient of about 18 years of age and under having a localized and non-metastatic tumor and receiving a dose of about 1 mg/kg to about 5 mg/kg or about 10 mg/m2 to about 300 mg/m2 per cycle of cisplatin, the method comprising administering about 5 g/m2 to about 25 g/m2 of sodium thiosulfate per cycle of the cisplatin about six hours after the administration of the cisplatin, wherein ototoxicity is determined by one or more criteria selected from:
• a). a reduction in hearing measured by a 20 dB loss at a single frequency;
• b). a reduction in hearing measured by a 10 dB loss at two consecutive frequencies;
• c). loss of response at three consecutive test frequencies where responses were previously obtained;
• d). a reduction in bilateral high-frequency hearing characterized by the criteria:
• i). a <40 dB hearing loss at all frequencies, which indicates a grade 0 or minimal hearing loss;
• ii). a >40 dB hearing loss at 8,000 Hz only, which indicates a grade 1 or mild hearing loss;
• iii). a >40 dB hearing loss at 4,000 Hz and above, which indicates a grade 2 or moderate hearing loss;
• iv). a >40 dB hearing loss at 2,000 Hz and above, which indicates a grade 3 or marked hearing loss;
• v). a >40 dB hearing loss at 1,000 Hz and above, which indicates a grade 4 or severe hearing loss;
• or
• e). a reduction in hearing characterized by the criteria:
• 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 a change in hearing is computed relative to baseline measures prior to the patient receiving a platinum based chemotherapeutic or sodium thiosulfate or both;
• and
• 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;
• and
• wherein the administration of sodium thiosulfate does not lead to substantively increased incidence of one or more adverse events comprising febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea.

A dosing regimen for treating a localized and non-metastatic tumor in a pediatric patient of about 18 years of age and under comprising:

• a). administering a dose of about 1 mg/kg to about 5 mg/kg or about 10 mg/m2 to about 300 mg/m2 per cycle of cisplatin;
• b). administering about 5 g/m2 to about 25 g/m2 of sodium thiosulfate per cycle of the cisplatin, wherein the sodium thiosulfate is administered from about 2 hours to about 6 hours after the administration of the cisplatin;
• and
• wherein the dosing regimen achieves a reduction in ototoxicity when dosed to a pediatric patient compared to a dosing regimen not including the sodium thiosulfate, which is dosed to a pediatric patient, wherein ototoxicity is determined by one or more criteria selected from:
• a). a reduction in hearing measured by a 20 dB loss at a single frequency;
• b). a reduction in hearing measured by a 10 dB loss at two consecutive frequencies;
• c). loss of response at three consecutive test frequencies where responses were previously obtained;
• d). a reduction in bilateral high-frequency hearing characterized by the criteria:
• i). a <40 dB hearing loss at all frequencies, which indicates a grade 0 or minimal hearing loss;
• ii). a ≥40 dB hearing loss at 8,000 Hz only, which indicates a grade 1 or mild hearing loss;
• iii). a ≥40 dB hearing loss at 4,000 Hz and above, which indicates a grade 2 or moderate hearing loss;
• iv). a ≥40 dB hearing loss at 2,000 Hz and above, which indicates a grade 3 or marked hearing loss;
• v). a ≥40 dB hearing loss at 1,000 Hz and above, which indicates a grade 4 or severe hearing loss;
• or
• e). a reduction in hearing characterized by the criteria:
• 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 a change in hearing is computed relative to baseline measures prior to the patient receiving a platinum based chemotherapeutic or sodium thiosulfate or both.