Clinical trial NCT02094625: NAC to Prevent Cisplatin-induced Hearing Loss
Official title: A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuroectodermal Tumors, Primitive
Liver Neoplasms
Osteosarcoma
Other Childhood Cancers Using Cisplatin-based Regimens
Keywords: Cisplatin
N-acetylcysteine
Hearing Loss
Otoprotection
Lead sponsor: Children's Hospital Los Angeles
Sponsor class: OTHER
First posted: 2014-03-24
Enrollment: 52
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Cisplatin is a key chemotherapy agent for the treatment of multiple childhood cancers but causes permanent hearing loss. This study investigates the drug N-acetylcysteine (NAC) to determine the dose necessary to protect hearing and also how well tolerated NAC is when combined with chemotherapy.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Target Serum Level NAC
timeFrame: On average up to 4 weeks from diagnosis
Secondary outcomes:
measure: Adverse events during infusion of NAC
timeFrame: Up to approximately 40 weeks from start of chemotherapy (regimen dependent)
measure: NAC Level
timeFrame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
measure: Hearing assessment
timeFrame: Up to approximately 40 weeks from start of chemotherapy
measure: Renal Toxicity
timeFrame: Up to approximately 40 weeks from start of chemotherapy
measure: Response of tumor to treatment
timeFrame: On average up to 15 weeks from start of chemotherapy (regimen dependent)
measure: Effect of Genotype on Hearing Loss and Hearing Protection
timeFrame: On average up to 15 weeks from start of chemotherapy
measure: Glutathione serum level
timeFrame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
Study officials:
affiliation: Children's Hospital Los Angeles
name: Etan Orgel, MD MS
role: PRINCIPAL_INVESTIGATOR
References: