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Neuroectodermal Tumors, PrimitivePhase 1NCT02094625

NAC to Prevent Cisplatin-induced Hearing Loss

A Phase 1 study testing N-Acetylcysteine in people with Neuroectodermal Tumors, Primitive and Liver Neoplasms, run by Children's Hospital Los Angeles at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
N-Acetylcysteine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
1 siteUnited States
Study dates
Mar 2016to Aug 2021
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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)

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

Other trials in United States

About this study

Official title: A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer

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.

Read the 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.

Being tested
N-Acetylcysteine
Keywords
Cisplatin, N-acetylcysteine, Hearing Loss, Otoprotection
Medical subject headings
Neuroectodermal Tumors, Primitive, Liver Neoplasms, Osteosarcoma, Hearing Loss

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • N-AcetylcysteineDrug

    Also called N-acteylcysteine, acteylcysteine injectable, Acetadote

    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.

Study groups in NCT02094625
Study groupRoleWhat they receive
N-Acetylcysteine InterventionExperimentalThis 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.
Receives: Drug: N-Acetylcysteine
Observation onlyNo interventionSubjects 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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: On average up to 4 weeks from diagnosis

Secondary outcomes (7)

  1. Adverse events during infusion of NAC

    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.

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

  2. NAC Level

    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.

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

  3. Hearing assessment

    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.

    Measured: Up to approximately 40 weeks from start of chemotherapy

  4. Renal Toxicity

    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

    Measured: Up to approximately 40 weeks from start of chemotherapy

  5. Response of tumor to treatment

    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

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

  6. Effect of Genotype on Hearing Loss and Hearing Protection

    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

    Measured: On average up to 15 weeks from start of chemotherapy

  7. Glutathione serum level

    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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Mar 2014 (estimated)
  2. Study startMar 2016
  3. Primary completionSep 2020
  4. Study completionAug 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
52 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02094625
Sponsor's protocol ID
CCI-14-00270
Status last verified
Apr 2023
First submitted
13 Mar 2014
Last updated
18 Apr 2023
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing N-Acetylcysteine in people with Neuroectodermal Tumors, Primitive and Liver Neoplasms, run by Children's Hospital Los Angeles at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Target Serum Level NAC (time frame: On average up to 4 weeks from diagnosis). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02094625.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2023.

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