NAC to Prevent Cisplatin-induced Hearing Loss

NCT02094625 | Completed Phase 1 DMC

• 1 other identifier: CCI-14-00270
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Cisplatin; N-acetylcysteine; Hearing Loss; Otoprotection

Outcome Measures

Primary Outcomes (1)

• Target Serum Level NAC

  Following the first dose of cisplatin, NAC will be administered as described below. A NAC level will then be measured immediately following this first dose of NAC to determine if the blood (serum) level reaches the threshold necessary for hearing protection.

  On average up to 4 weeks from diagnosis

Secondary Outcomes (7)

• Adverse events during infusion of NAC

  Up to approximately 40 weeks from start of chemotherapy (regimen dependent)

• NAC Level

  -6,0, 0.5, and 4 hours from start of first NAC dose (intervention)

• Hearing assessment

  Up to approximately 40 weeks from start of chemotherapy

• Renal Toxicity

  Up to approximately 40 weeks from start of chemotherapy

• Response of tumor to treatment

  On average up to 15 weeks from start of chemotherapy (regimen dependent)

Study Arms (2)

N-Acetylcysteine Intervention

EXPERIMENTAL

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.

Drug: N-Acetylcysteine

Observation only

NO INTERVENTION

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.

Interventions

N-Acetylcysteine 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.

Also known as: N-acteylcysteine, acteylcysteine injectable, Acetadote

N-Acetylcysteine Intervention

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead

Study Sites (1)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

MeSH Terms

Conditions

Neuroectodermal Tumors, Primitive; Liver Neoplasms; Osteosarcoma; Hearing Loss

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Etan Orgel, MD MS

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical Pediatrics

Study Record Dates

• First Submitted: March 13, 2014
• First Posted: March 24, 2014
• Study Start: March 1, 2016
• Primary Completion: September 1, 2020
• Study Completion: August 1, 2021
• Last Updated: April 18, 2023

Record last verified: 2023-04

Locations

US (1)