Back to resultsNAC to Prevent Cisplatin-induced Hearing Loss
Primary Purpose
Neuroectodermal Tumors, Primitive, Liver Neoplasms, Osteosarcoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
N-Acetylcysteine
Sponsored by
About this trial
This is an interventional treatment trial for Neuroectodermal Tumors, Primitive focused on measuring Cisplatin, N-acetylcysteine, Hearing Loss, Otoprotection
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
Sites / Locations
- Childrens Hospital Los Angeles
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
N-Acetylcysteine Intervention
Observation only
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
NAC Level
A NAC serum level will be measured surrounding the first dose of NAC at 4 times:
pre-cisplatin (baseline)
following cisplatin/before NAC
immediately following NAC (primary aim)
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
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
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
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
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
Glutathione serum levels will be measured at times corresponding to NAC levels surrounding the first dose of NAC at 4 times:
pre-cisplatin (baseline)
following cisplatin/before NAC
immediately following NAC (primary aim)
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.
Full Information
NCT ID
NCT02094625
First Posted
March 13, 2014
Last Updated
April 14, 2023
Sponsor
Children's Hospital Los Angeles
1. Study Identification
Unique Protocol Identification Number
NCT02094625
Brief Title
NAC to Prevent Cisplatin-induced Hearing Loss
Official Title
A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
March 2016 (Actual)
Primary Completion Date
September 2020 (Actual)
Study Completion Date
August 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's Hospital Los Angeles
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroectodermal Tumors, Primitive, Liver Neoplasms, Osteosarcoma, Other Childhood Cancers Using Cisplatin-based Regimens
Keywords
Cisplatin, N-acetylcysteine, Hearing Loss, Otoprotection
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
52 (Actual)
8. Arms, Groups, and Interventions
Arm Title
N-Acetylcysteine Intervention
Arm Type
Experimental
Arm Description
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.
Arm Title
Observation only
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
N-Acetylcysteine
Other Intervention Name(s)
N-acteylcysteine, acteylcysteine injectable, Acetadote
Intervention Description
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.
Primary Outcome Measure Information:
Title
Target Serum Level NAC
Description
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.
Time Frame
On average up to 4 weeks from diagnosis
Secondary Outcome Measure Information:
Title
Adverse events during infusion of NAC
Description
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.
Time Frame
Up to approximately 40 weeks from start of chemotherapy (regimen dependent)
Title
NAC Level
Description
A NAC serum level will be measured surrounding the first dose of NAC at 4 times:
pre-cisplatin (baseline)
following cisplatin/before NAC
immediately following NAC (primary aim)
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.
Time Frame
-6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
Title
Hearing assessment
Description
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.
Time Frame
Up to approximately 40 weeks from start of chemotherapy
Title
Renal Toxicity
Description
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
Time Frame
Up to approximately 40 weeks from start of chemotherapy
Title
Response of tumor to treatment
Description
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
Time Frame
On average up to 15 weeks from start of chemotherapy (regimen dependent)
Title
Effect of Genotype on Hearing Loss and Hearing Protection
Description
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
Time Frame
On average up to 15 weeks from start of chemotherapy
Title
Glutathione serum level
Description
Glutathione serum levels will be measured at times corresponding to NAC levels surrounding the first dose of NAC at 4 times:
pre-cisplatin (baseline)
following cisplatin/before NAC
immediately following NAC (primary aim)
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.
Time Frame
-6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Etan Orgel, MD MS
Organizational Affiliation
Children's Hospital Los Angeles
Official's Role
Principal Investigator
Facility Information:
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
12. IPD Sharing Statement
Learn more about this trial
NAC to Prevent Cisplatin-induced Hearing Loss
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