A Dose-Finding Study of N-Acetylcysteine (NAC) to Prevent Cisplatin-induced Hearing Loss in Children With Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Target Serum Level NAC
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
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.
干预措施: N-Acetylcysteine (Drug)
结局指标
主要结局
Target Serum Level NAC
时间窗: 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.
次要结局
- Hearing assessment(Up to approximately 40 weeks from start of chemotherapy)
- Renal Toxicity(Up to approximately 40 weeks from start of chemotherapy)
- Response of tumor to treatment(On average up to 15 weeks from start of chemotherapy (regimen dependent))
- NAC Level(-6,0, 0.5, and 4 hours from start of first NAC dose (intervention))
- Adverse events during infusion of NAC(Up to approximately 40 weeks from start of chemotherapy (regimen dependent))
- Effect of Genotype on Hearing Loss and Hearing Protection(On average up to 15 weeks from start of chemotherapy)
- Glutathione serum level(-6,0, 0.5, and 4 hours from start of first NAC dose (intervention))
研究者
Etan Orgel
Assistant Professor of Clinical Pediatrics
Children's Hospital Los Angeles