- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02094625
NAC to Prevent Cisplatin-induced Hearing Loss
A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90027
- Childrens Hospital Los Angeles
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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. |
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:
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Target Serum Level NAC
Time Frame: On average up to 4 weeks from diagnosis
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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.
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On average up to 4 weeks from diagnosis
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adverse events during infusion of NAC
Time Frame: Up to approximately 40 weeks from start of chemotherapy (regimen dependent)
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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.
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Up to approximately 40 weeks from start of chemotherapy (regimen dependent)
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NAC Level
Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
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A NAC serum level will be measured surrounding the first dose of NAC at 4 times:
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. |
-6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
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Hearing assessment
Time Frame: Up to approximately 40 weeks from start of chemotherapy
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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.
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Up to approximately 40 weeks from start of chemotherapy
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Renal Toxicity
Time Frame: Up to approximately 40 weeks from start of chemotherapy
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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
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Up to approximately 40 weeks from start of chemotherapy
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Response of tumor to treatment
Time Frame: On average up to 15 weeks from start of chemotherapy (regimen dependent)
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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
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On average up to 15 weeks from start of chemotherapy (regimen dependent)
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Effect of Genotype on Hearing Loss and Hearing Protection
Time Frame: On average up to 15 weeks from start of chemotherapy
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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
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On average up to 15 weeks from start of chemotherapy
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Glutathione serum level
Time Frame: -6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
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Glutathione serum levels will be measured at times corresponding to NAC levels surrounding the first dose of NAC at 4 times:
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. |
-6,0, 0.5, and 4 hours from start of first NAC dose (intervention)
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Nervous System Diseases
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Neurologic Manifestations
- Digestive System Neoplasms
- Liver Diseases
- Otorhinolaryngologic Diseases
- Neoplasms, Neuroepithelial
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Ear Diseases
- Sensation Disorders
- Neoplasms, Bone Tissue
- Neoplasms, Connective Tissue
- Sarcoma
- Hearing Disorders
- Liver Neoplasms
- Hearing Loss
- Osteosarcoma
- Deafness
- Neuroectodermal Tumors
- Neuroectodermal Tumors, Primitive
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Protective Agents
- Respiratory System Agents
- Antioxidants
- Antidotes
- Free Radical Scavengers
- Expectorants
- Acetylcysteine
- N-monoacetylcystine
Other Study ID Numbers
- CCI-14-00270
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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