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Acetylcysteine for the Prevention of Cisplatin-Induced Hearing Loss in Children with Newly Diagnosed Localized Cancer

Trial Status: Closed to Accrual

This phase I trial evaluates 3 different doses of acetylcysteine (NAC) to find the best dose that may prevent inner ear damage from cisplatin in children with cancer that is newly diagnosed and has not spread to other parts of the body (localized). Permanent hearing loss is a common severe side effect in patients who receive cisplatin for cancer therapy. NAC is a drug used in children and adolescents to protect the liver and kidneys from damage caused by medicine overdoses and other toxins. NAC may also help to protect the inner ear from damage caused by cisplatin without affecting how well cisplatin kills cancer.

Inclusion Criteria

  • Have a new diagnosis of a localized malignancy * Surgery, radiation therapy, and non-platinum based chemotherapy, are allowed prior to enrollment. Low-dose/non-myeloablative carboplatin during the period of radiation therapy is permitted prior to enrollment * Tumor diagnosis to have been previously confirmed by the 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
  • Have a planned treatment course to include at least two cycles of cisplatin
  • Total cumulative dose of planned cisplatin must be >= 200 mg/m^2 (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 for =< 2 consecutive days per cycle
  • Are anticipated to be able to comply with end-of-therapy audiology assessment by at least one of the modalities (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)
  • Hepatic, biliary, cardiac, or bone marrow function adequate for chemotherapy as per patient’s treatment regimen. There are no additional protocol-specific restrictions for these markers
  • Adequate renal function as defined by a glomerular filtration rate (GFR) >= 60 ml/min/1.73m^2 or a serum creatinine < 1.5 x upper limit of normal for age
  • No pre-existing risk for arrhythmia as defined by: * Absence of arrhythmia on electrocardiogram as indicated by normal sinus rhythm and corrected QT interval (QTc) < 500 * No known previous history of congenital arrhythmia (e.g. Wolf-Parkinson-White)
  • Patients with any baseline hearing status are eligible for study (as long as they can comply with the study primary aims of assessing toxicity and dose-response)
  • OBSERVATION-ONLY: Subjects who meet the following criteria will be eligible for an “observation-only” group in which they will participate in the study only for collection of research specimens and collection of information obtained per standard of care tests: * Are otherwise eligible per full criteria above but choose not to receive study medication on the treatment arm Or * Meet eligibility criteria above with the following exceptions (as no treatment will be given to the observation group): ** Disseminated disease is permitted ** No organ function requirements ** No moderate or severe persistent asthma restrictions ** No pregnancy or breast feeding mothers exclusion ** No performance status (Karnofsky Lansky score) exclusion ** No documented hypersensitivity or allergy to previous NAC infusion exclusion

Exclusion Criteria

  • Moderate or severe persistent asthma as defined by the latest recommendations from the National Heart, Lung, and Blood Institute (NHLBI) (definition includes daily asthma exacerbations with need for rescue medication) or an overnight hospitalization for asthma exacerbation within the previous 28 days
  • Karnofsky or Lansky score < 50%
  • Disseminated disease (e.g. metastatic tumor, lepto-meningeal spread)
  • Pregnancy or breast feeding mothers * In female patients post-menarche with germ cell tumor and + beta human chorionic gonadotropin (B-HCG), documentation of lack of pregnancy by other method is recommended although attestation by attending of record (or designee) is acceptable as well
  • Documented hypersensitivity or allergy to previous NAC infusion
  • No restrictions or specification of chemotherapy regimens or clinician-prescribed hematopoietic growth factors
  • May not be receiving amifostine for otoprotection (due to the timing of infusion and associated metabolic complications)
  • There is no restriction to the usage of sodium thiosulfate (STS) for patients enrolled on this protocol as long as STS is administered as per ACCL0431 (or SIOPEL 6) starting 6 hours after completion of cisplatin infusion (i.e. must follow NAC)
  • There are no restrictions on use of additional intravenous or oral antioxidants (data to be collected)
  • As the toxicity on this protocol is infusion-related, subjects may be receiving concurrent therapy regimens inclusive of investigational agents for the treatment of their underlying malignancy if the agent is not given during the time period from start of cisplatin through conclusion of blood tests (i.e. the acute assessment period for this protocol) and as determined by the investigators of the concurrent therapeutic protocol

California

Los Angeles
Children's Hospital Los Angeles
Status: CLOSED_TO_ACCRUAL
Contact: Etan Orgel
Phone: 323-361-2672

PRIMARY OBJECTIVES:

I. To determine the translational dose of NAC in children needed to achieve peak serum concentrations associated with otoprotection in the rat model.

II. To assess the acute toxicity of NAC in children receiving cisplatin as part of multiple-agent regimens.

SECONDARY OBJECTIVES:

I. To evaluate glutathione and other biomarkers in the blood relevant to the proposed mechanism of NAC’s otoprotection and cisplatin ototoxicity.

II. To explore the prevalence and influence of specific genetic polymorphisms implicated in both cisplatin ototoxicity and the proposed NAC mechanism of action.

III. To evaluate NAC for preliminary evidence of efficacy through comparison of the prevalence and kinetics of ototoxicity to a recent historical cohort.

IV. To explore whether NAC ameliorates other specific cisplatin toxicities (i.e. nephrotoxicity and treatment-delays due to myelosuppression) including a comparison of percentage target dosing of cisplatin delivered versus a recent historical cohort.

V. To evaluate tumor-specific early response to chemotherapy for any concern for tumor protection by NAC.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 arms.

ARM I: Beginning 4 hours after completion of each standard of care cisplatin infusion, patients receive NAC intravenously (IV) over 60 minutes in the absence of unacceptable toxicity.

ARM II: Patients undergo observation.

After completion of study treatment, patients are followed up for 3 years.

Trial Phase Phase I

Trial Type Supportive care

Lead Organization
Children's Hospital Los Angeles

Principal Investigator
Etan Orgel

  • Primary ID CHLA-14-00270
  • Secondary IDs NCI-2020-07437
  • Clinicaltrials.gov ID NCT02094625