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Trial record 2 of 3 for:    key adverse events and childhood cancer | Open Studies

NAC to Prevent Cisplatin-induced Hearing Loss

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by Children's Hospital Los Angeles
Information provided by (Responsible Party):
Etan Orgel, Children's Hospital Los Angeles Identifier:
First received: March 13, 2014
Last updated: March 18, 2016
Last verified: March 2016
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.

Condition Intervention Phase
Neuroectodermal Tumors, Primitive
Liver Neoplasms
Neoplasms, Germ Cell and Embryonal
Other Childhood Cancers Using Cisplatin-based Regimens
Drug: N-Acetylcysteine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer

Resource links provided by NLM:

Further study details as provided by Children's Hospital Los Angeles:

Primary Outcome Measures:
  • Target Serum Level NAC [ Time Frame: On average up to 8 weeks from diagnosis ] [ Designated as safety issue: No ]
    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.

Secondary Outcome Measures:
  • Adverse events during infusion of NAC [ Time Frame: Up to approximately 40 weeks from start of chemotherapy (regimen dependent) ] [ Designated as safety issue: Yes ]
    Subjects will be monitored during and after each NAC infusion to determine how well they tolerate the drug. Infusion rate related and spontaneously resolving "anaphylactoid" reactions are the most common reported toxicity and will be closely monitored. Most subjects will receive 3 cycles of cisplatin and NAC, typically within the first 15 weeks of starting chemotherapy. Subjects who continue to receive cisplatin and NAC for additional cycles will continue to be monitored.

  • NAC Level [ Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention) ] [ Designated as safety issue: No ]

    A NAC serum level will be measured surrounding the first dose of NAC at 4 times:

    1. pre-cisplatin (baseline)
    2. following cisplatin/before NAC
    3. immediately following NAC (primary aim)
    4. delayed four hours following NAC

    For those in the non-intervention arm, NAC serum levels will be measured at corresponding times as determined by the start of the cisplatin infusion.

  • Hearing assessment [ Time Frame: Up to approximately 40 weeks from start of chemotherapy ] [ Designated as safety issue: No ]
    Routinely performed hearing assessments will be analyzed at the end of therapy as compared to a historical cohort, non-treated, and to patient's baseline (if available) to evaluate for any trend toward a protective effect from NAC.

  • Renal Toxicity [ Time Frame: Up to approximately 40 weeks from start of chemotherapy ] [ Designated as safety issue: No ]
    Information regarding renal toxicity due to cisplatin will be collected at end of therapy and compared to historical rates and non-treated patients to evaluate a potential protective effect by NAC

  • Response of tumor to treatment [ Time Frame: On average up to 15 weeks from start of chemotherapy (regimen dependent) ] [ Designated as safety issue: No ]
    Early indicators of tumor response to cisplatin-based chemotherapy (e.g. percent necrosis in resected tumors, early remission rates, etc) will be informally evaluated in comparison to historical data for any evidence NAC decreases efficacy of the chemotherapy

  • Effect of Genotype on Hearing Loss and Hearing Protection [ Time Frame: On average up to 15 weeks from start of chemotherapy ] [ Designated as safety issue: No ]
    Saliva/cheek swabs will be collected one-time for genotype analysis to examine the influence of glutathione polymorphisms on cisplatin-induced hearing loss and NAC hearing protection

  • Glutathione serum level [ Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention) ] [ Designated as safety issue: No ]

    Glutathione serum levels will be measured at times corresponding to NAC levels surrounding the first dose of NAC at 4 times:

    1. pre-cisplatin (baseline)
    2. following cisplatin/before NAC
    3. immediately following NAC (primary aim)
    4. delayed four hours following NAC

    For those in the non-intervention arm, serum levels will again be measured at corresponding times as determined by the start of the cisplatin infusion.

Estimated Enrollment: 30
Study Start Date: March 2016
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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. The selected dose will then be tested further in an expansion cohort of an additional 6 subjects.
Drug: N-Acetylcysteine

NAC will be administered intravenously over ~30 minutes starting 4 hours following completion of cisplatin for the first 3 cycles of chemotherapy. Patients will have the option to continue with NAC for any remaining cycles.

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.

Other Names:
  • N-acteylcysteine
  • acteylcysteine injectable
  • Acetadote
No Intervention: 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 6 children will be enrolled over the course of the study.

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.


Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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 high-risk neuroblastoma, hepatoblastoma, germ cell tumor, 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).
  • Planned cisplatin dose to be infused over ≤6 hours
  • 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:

  • Inadequate cardiac function as defined by (A) echocardiogram with left ventricular shortening fraction (LVSF) < 28% or ejection fraction (EF) < 55% and/or qualitatively abnormal systolic function, (B) presence of serious arrhythmia on electrocardiogram, or (C) corrected QT interval >480.
  • previous history of congestive heart failure or congenital arrhythmia (e.g. Wolf-Parkinson-White)
  • Hepatic, biliary, 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02094625

Contact: Hema Sukhija 323-361-6015
Contact: Lakshmi Damerla 323-361-8359

United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Principal Investigator: Etan Orgel, MD MS         
Sub-Investigator: David R Freyer, DO MS         
Sponsors and Collaborators
Children's Hospital Los Angeles
Principal Investigator: Etan Orgel, MD MS Children's Hospital Los Angeles
  More Information

Responsible Party: Etan Orgel, Assistant Professor of Clinical Pediatrics, Children's Hospital Los Angeles Identifier: NCT02094625     History of Changes
Other Study ID Numbers: CCI-14-00270 
Study First Received: March 13, 2014
Last Updated: March 18, 2016
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Children's Hospital Los Angeles:
Hearing Loss

Additional relevant MeSH terms:
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Liver Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Digestive System Neoplasms
Neoplasms by Site
Hearing Loss
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Digestive System Diseases
Liver Diseases
N-monoacetylcystine processed this record on October 21, 2016