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

1 : A method of reducing ototoxicity in a pediatric patient having a cancer and receiving a platinum based chemotherapeutic comprising administering an effective amount of sodium thiosulfate to the pediatric patient.

2 - 6 . (canceled)

7 : The method of claim 1 , wherein the pediatric patient administered sodium thiosulfate is about 20% to about 75% less likely to experience ototoxicity than a pediatric patient not administered sodium thiosulfate.

8 : The method of claim 7 , wherein the pediatric patient administered sodium thiosulfate is about 50% less likely to experience ototoxicity than a pediatric patient not administered sodium thiosulfate.

9 : The method of claim 1 , wherein the ototoxicity comprises hearing loss, dysequilibrium, tinnitus, or hearing sensitivity, or combinations thereof.

10 : The method of claim 1 , wherein the platinum based chemotherapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

11 : The method of claim 10 , wherein the platinum based chemotherapeutic is cisplatin.

12 - 18 . (canceled)

19 : The method of claim 1 , wherein the pediatric patient is 1 week of age to 18 years of age.

20 : The method of claim 1 , wherein the pediatric patient is about 12 years of age or less.

21 : The method of claim 1 , wherein the pediatric patient is about 5 years of age or less.

22 - 23 . (canceled)

24 : The method of claim 1 , wherein the sodium thiosulfate is administered prior to, concurrently with, or after the administration of the platinum based chemotherapeutic.

25 : The method of claim 1 , wherein the sodium thiosulfate is administered about 0.5 hours to about 10 hours after the administration of the platinum based chemotherapeutic.

26 - 28 . (canceled)

29 : The method of claim 1 , wherein the ototoxicity is determined by one or more criteria comprising: a tinnitus functional index, Brock grading, American Speech-Language-Hearing Association criteria, or International Society of Pediatric Oncology Boston Ototoxicity Scale.

30 : The method of claim 1 , wherein the ototoxicity is determined by measuring a hearing loss at one or more frequencies comprising 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, or 8,000 Hz or a combination of frequencies thereof, 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.

31 : The method of claim 11 , wherein the ototoxicity is determined by one or more criteria comprising:

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:

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:

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, or

f). an improvement in a tinnitus functional index; and

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.

32 . (canceled)

33 : The method of claim 1 , wherein the administration of sodium thiosulfate does not lead to increased serum creatinine or a reduction in glomerular filtration rate compared to a pediatric patient not administered sodium thiosulfate.

34 : The method of claim 1 , wherein the administration of sodium thiosulfate does not affect relapse free survival or overall survival compared to a pediatric patient not administered sodium thiosulfate.

35 : The method of claim 1 , wherein the administration of sodium thiosulfate does not lead to increased incidence of one or more adverse events comprising febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea.

36 : The method of claim 1 , wherein ototoxicity is measured at a time of at least 4 weeks following the administration of the platinum based chemotherapeutic and sodium thiosulfate.

37 : A dosing regimen for treating hepatoblastoma in a pediatric patient comprising:

1), administering 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 of cisplatin;

2) administering about 5 g/m 2 to about 25 g/m 2 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.

38 : A method of reducing ototoxicity in a pediatric patient of about 12 years of age and under having a standard risk or an intermediate risk hepatoblastoma and receiving 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 of cisplatin, the method comprising administering about 5 g/m 2 to about 25 g/m 2 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.