Working... Menu

NAC to Prevent Cisplatin-induced Hearing Loss

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02094625
Recruitment Status : Recruiting
First Posted : March 24, 2014
Last Update Posted : January 30, 2019
Information provided by (Responsible Party):
Etan Orgel, Children's Hospital Los Angeles

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.

Condition or disease Intervention/treatment Phase
Neuroectodermal Tumors, Primitive Liver Neoplasms Osteosarcoma Other Childhood Cancers Using Cisplatin-based Regimens Drug: N-Acetylcysteine Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : March 2016
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : October 2020

Arm Intervention/treatment
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.

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

Drug: 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.

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 36 children will be enrolled over the course of the study.

Primary Outcome Measures :
  1. Target Serum Level NAC [ Time Frame: On average up to 4 weeks from diagnosis ]
    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 :
  1. Adverse events during infusion of NAC [ Time Frame: Up to approximately 40 weeks from start of chemotherapy (regimen dependent) ]
    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.

  2. NAC Level [ Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention) ]

    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.

  3. Hearing assessment [ Time Frame: Up to approximately 40 weeks from start of chemotherapy ]
    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.

  4. Renal Toxicity [ Time Frame: Up to approximately 40 weeks from start of chemotherapy ]
    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

  5. Response of tumor to treatment [ Time Frame: On average up to 15 weeks from start of chemotherapy (regimen dependent) ]
    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

  6. Effect of Genotype on Hearing Loss and Hearing Protection [ Time Frame: On average up to 15 weeks from start of chemotherapy ]
    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

  7. Glutathione serum level [ Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention) ]

    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.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02094625

Layout table for location contacts
Contact: Mary Morrison-Barrios 323-361-8897
Contact: Katie Villabroza 323-361-2121

Layout table for location information
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
Layout table for investigator information
Principal Investigator: Etan Orgel, MD MS Children's Hospital Los Angeles

Layout table for additonal 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
First Posted: March 24, 2014    Key Record Dates
Last Update Posted: January 30, 2019
Last Verified: January 2019

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

Additional relevant MeSH terms:
Layout table for MeSH terms
Hearing Loss
Hearing Disorders
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Liver Neoplasms
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases