NAC to Prevent Cisplatin-induced Hearing Loss

The study is a dose-finding study of N-acetylcysteine (NAC) to protect hearing in children
receiving cisplatin for the treatment of their cancer. NAC also has potential to protect the
kidneys from cisplatin toxicity.

The study uses a 3+3 dose-escalation scheme to determine the dose of NAC necessary to achieve
serum levels consistent with hearing protection in pre-clinical animal models. Three dose
levels are predefined. Once the maximum tolerated dose is determined, an expansion cohort
will then be enrolled to further evaluate tolerability as well as intra-patient and
inter-patient variability in achieved serum levels. An option to enroll in a separate arm for
study assessments only is available for those who do not wish to receive NAC. Hearing loss in
the cohort will be assessed in the entire cohort in comparison to historical and non-treated
children to evaluate for trends toward efficacy.

Inclusion Criteria:

- Are between 1 and 21 years of age (inclusive) at time of diagnosis of underlying
malignancy

- Have a new diagnosis of a localized malignancy with a planned treatment course to
include at least two cycles of cisplatin

- Diagnosis to be assigned by oncology attending of record (may be reported via
designee), histological diagnosis does not need to be confirmed separately

- Most common but not exclusive diagnoses consist of hepatoblastoma, medulloblastoma,
osteosarcoma

- Total cumulative dose of planned cisplatin must be >200 mg/m2 (or 6.67 mg/kg
equivalent for infants requiring weight-based dosing. Conversion factor used is 30:1).

- Cisplatin must be delivered over <3 days

- Planned cisplatin dose to be infused over ≤6 hours for ≤2 days per cycle

- Are anticipated to be able to comply with end-of-therapy audiology assessment (note
that hearing assessments are performed per routine clinical care in children receiving
cisplatin and consist of an audiogram or auditory brainstem response, and
distortion-product otoacoustic emissions)

- Patients with any hearing status are eligible for study (as long as they can comply
with the study primary aims of assessing toxicity and dose-response)

Exclusion Criteria:

- no preexisting risk of serious arrhythmia as defined by (a) normal sinus rhythm on
electrocardiogram and corrected QT interval <500 and (b) no previous history of
congenital arrhythmia (e.g. Wolf-Parkinson-White)

- Hepatic, biliary, cardiac, or bone marrow function inadequate for chemotherapy as per
patient's treatment regimen. There are no additional protocol-specific restrictions
for these markers.

- Moderate or Severe Persistent Asthma as defined by the latest recommendations from the
National Heart Lung and Blood Institute definition includes daily asthma exacerbation
with need for rescue medication) or an overnight hospitalization for asthma
exacerbation within the previous 28 days

- Disseminated disease (e.g. lepto-meningeal spread, tumor metastases)

- Karnofsky or Lansky score <50%

- Pregnancy or breast-feeding mothers

- Documented hypersensitivity or allergy to previous NAC infusion