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

Abstract

Described herein is a method for eliminating or reducing ototoxicity in patients receiving a platinum based chemotherapeutic. In particular, are methods of reducing ototoxicity in a pediatric patient. The methods described herein include administering an effective amount of sodium thiosulfate to a patient in need thereof to reduce ototoxicity.

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.