NAC to Prevent Cisplatin-induced Hearing Loss

NCT ID: NCT02094625

Last Updated: 2023-04-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-31
• Study Completion Date: 2021-08-31

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.

Conditions

Neuroectodermal Tumors, Primitive; Liver Neoplasms; Osteosarcoma; Other Childhood Cancers Using Cisplatin-based Regimens

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

N-Acetylcysteine Intervention

This is a dose-finding study using a traditional 3+3 dose escalation scheme. Up to 18 subjects (3 dose levels as per below) will be enrolled to determine the maximum tolerated dose (MTD). The MTD is defined as per traditional 3+3 criteria of less than or equal to one dose-limiting toxicity at the dose level. Once the MTD is determined, subjects will be equally distributed at the "safe" dose levels (less than or equal to the MTD) to determine the optimum dose to achieve NAC levels in the blood necessary for hearing protection.

As of August 2018: The dose-escalation phase was completed and dose-level three was selected for expansion in 9 subjects.

Group Type: EXPERIMENTAL

N-Acetylcysteine

Intervention Type: DRUG

NAC will be administered intravenously over ~60 minutes starting 4 hours following completion of cisplatin chemotherapy.

Three dose levels have been pre-determined:

Dose Level 1: 225 mg/kg Dose Level 2: 300 mg/kg Dose Level 3: 450 mg/kg

Should Dose Level 3 exceed the MTD, the study will examine blood levels of NAC and if below the target blood level necessary for hearing protection, the study will "de-escalate" from Dose Level 3 to an intermediate Dose Level 2.5 and test a dose of 375 mg/kg.

As of August 2018: Dose escalation completed with MTD not reached. Dose level 3 (450mg/kg) selected for expansion with NAC.

Observation only

Subjects who are ineligible to receive the study drug NAC will have the option to enroll for study assessments only including laboratory testing and hearing assessments identical to the experimental intervention arm. This is a "cohort of convenience" for which we anticipate up to 36 children will be enrolled over the course of the study.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

N-Acetylcysteine

NAC will be administered intravenously over ~60 minutes starting 4 hours following completion of cisplatin chemotherapy.

Three dose levels have been pre-determined:

Dose Level 1: 225 mg/kg Dose Level 2: 300 mg/kg Dose Level 3: 450 mg/kg

Should Dose Level 3 exceed the MTD, the study will examine blood levels of NAC and if below the target blood level necessary for hearing protection, the study will "de-escalate" from Dose Level 3 to an intermediate Dose Level 2.5 and test a dose of 375 mg/kg.

As of August 2018: Dose escalation completed with MTD not reached. Dose level 3 (450mg/kg) selected for expansion with NAC.

Intervention Type: DRUG

Other Intervention Names

N-acteylcysteine; acteylcysteine injectable; Acetadote

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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Etan Orgel

Assistant Professor of Clinical Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Etan Orgel, MD MS

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Los Angeles

Locations

Childrens Hospital Los Angeles

Los Angeles, California, United States

Countries

United States

Other Identifiers

CCI-14-00270

Identifier Type: -

Identifier Source: org_study_id