Phase II Trial of Nicotinamide Riboside for Relief of Taxane-Induced Sensory Neuropathy

烟酰胺核苷缓解紫杉烷引起的感觉神经病的 II 期试验

• 批准号: 9336864
• 负责人: DONNA L HAMMOND
• 金额: $ 12.87万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336864
• 关键词: Address; Adjuvant Therapy; Afferent Neurons; Aftercare; Blood; Breast Cancer Patient; Cancer Patient; Cancer Survivor; Chemotherapy-induced peripheral neuropathy; Common Terminology Criteria for Adverse Events; Data; Development; Dimensions; Dose; Dose-Limiting; Drug Kinetics; Evidence based treatment; Fiber; Goals; Gynecologic Oncology Group; Healthcare; Hypersensitivity; Incidence; Infusion procedures; Investigation; Malignant Neoplasms; Mechanics; Monitor; NADP; Nature; Neoadjuvant Therapy; Neurons; Oncologist; Outcome; Outcome Measure; Paclitaxel; Pain; Patient Outcomes Assessments; Patients; Peripheral Nervous System Diseases; Pharmacotherapy; Phase II Clinical Trials; Phase III Clinical Trials; Plasma; Population; Probability; Quality of life; Questionnaires; Reporting; Research; Rodent Model; Severities; Spinal Ganglia; Statistical Data Interpretation; Therapeutic Agents; Time; Treatment Protocols; Vitamins; Work; base; cancer diagnosis; cancer therapy; chemotherapy; design; efficacy trial; evidence base; improved functioning; injured; malignant breast neoplasm; neurotoxicity; nicotinamide-beta-riboside; oncology; open label; phase 3 study; phase II trial; pre-clinical; prevent; primary outcome; secondary outcome; sensory neuropathy; taxane; tool

Chemotherapy is frequently accompanied by peripheral neuropathies so painful and debilitating that it may be necessary to reduce the dose of agent, delay one or more cycles of chemotherapy, or even cease treatment. Furthermore, the peripheral neuropathies can worsen after treatment has ended and may not resolve with time. Both the dose-limiting nature and the persistence of chemotherapy-induced peripheral neuropathies (CIPN) are significant health care problems. There are few - if any - evidence-based therapies for the relief of CIPN. The long term goal of this research team is to identify a new strategy to alleviated CIPN in cancer patients, resulting in a meaningful improvement in their quality of life and the ability to sustain better and longer treatment. Here we propose a phase II clinical trial of the efficacy of nicotinamide riboside (NR), a naturally occurring vitamin precursor of NAD+, as a therapeutic agent. This proposal is based on the hypothesis that paclitaxel injures primary afferent neurons by reducing NAD+ in these neurons and their fibers. Our preclinical data demonstrate that paclitaxel does indeed decrease levels of NAD+ in dorsal root ganglia and that NR protects neuronal NAD+ in the face of intense chemotherapy treatment. Moreover, pre- treatment with NR protects against, and post-treatment with NR reverses, the mechanical hypersensitivity and the aversive dimension of pain in a rodent model of CIPN induced by paclitaxel. The specific aim of this proposal is to evaluate if daily dosing of NR prevents progressive worsening of sensory neuropathy in patients undergoing adjuvant or neo-adjuvant therapy with paclitaxel or nab-paclitaxel for the treatment of stage 1-3 breast cancer. The primary outcome measure is the change in the grade of sensory neuropathy between the baseline assessment and the 8th day of NR treatment after the final (i.e.12th) taxane infusion as determined by the CTCAE questionnaire. Secondary outcome measures are incidence of dose reduction, actual vs planned cumulative dose of paclitaxel administered, percentage of patients with dose reduction, and patient-reported function. This trial will be an open-label study in which all patients receive NR. Comparisons will be made to historical data on severity and progression in this population. Additional analyses will confirm that NR increases levels of NAD+ or its metabolite NAAD in blood, and does not interfere with the pharmaco- kinetics of paclitaxel. This phase II clinical trial will provide preliminary data as to whether NR treatment prevents a progressive worsening of CIPN and enables patients to complete the chemotherapy treatment without a reduction in dose of paclitaxel. It will also generate preliminary data correlating efficacy to an increase in NAD+ levels. This work will drive large Phase III studies of NR in the treatment of CIPN, and the discovery of a new pharmacotherapy for a significant unmet need in oncology. The findings have great potential to transform the practice of oncology with a therapy that results in a meaningful improvement in the patient's quality of life and the ability to complete optimal chemotherapy treatment regimens.

化疗经常伴随着周围神经病变，如此痛苦和衰弱， 这是减少药剂剂量、延迟一个或多个化疗周期或甚至停止治疗所必需的。 此外，周围神经病变在治疗结束后可能恶化，并且可能不会随着时间的推移而消退。 时间化疗诱导的周围神经病变的剂量限制性和持续性 （CIPN）是严重的卫生保健问题。很少有-如果有的话-以证据为基础的治疗方法来缓解 CIPN。该研究小组的长期目标是确定一种新的策略来减轻癌症中的CIPN 患者，导致他们的生活质量和维持更好的能力有意义的改善， 更长的治疗。在这里，我们提出了烟酰胺核苷（NR）的疗效的II期临床试验， NAD+的天然存在的维生素前体，作为治疗剂。这项建议是根据 紫杉醇通过减少这些神经元中的NAD+而损伤初级传入神经元的假说及其 纤维我们的临床前数据表明，紫杉醇确实降低了背根中NAD+的水平 神经节和NR保护神经元NAD+在面对强烈的化疗治疗。此外，预- NR治疗可预防机械超敏反应，NR治疗后可逆转机械超敏反应， 以及紫杉醇诱导的CIPN啮齿动物模型中疼痛的厌恶维度。其具体目的是 建议评估NR每日给药是否可预防感觉神经病变的进行性恶化， 接受紫杉醇或nab-紫杉醇辅助或新辅助治疗以治疗 1-3期乳腺癌。主要的结果测量是感觉神经病变等级的变化 基线评估与末次（即第12次）紫杉烷输注后NR治疗第8天之间， 通过CTCAE问卷确定。次要结局指标是剂量减少的发生率， 紫杉醇的实际与计划累积给药剂量，剂量减少的患者百分比，以及 患者报告功能。本试验是一项开放标签研究，所有患者均接受NR治疗。比较 将对该人群中严重程度和进展的历史数据进行分析。进一步的分析将证实 NR增加血液中NAD+或其代谢物NAAD的水平，并且不干扰药理作用。 紫杉醇的动力学这项II期临床试验将提供关于NR治疗是否 防止CIPN的进行性恶化，并使患者能够完成化疗治疗 而不减少紫杉醇的剂量。它还将生成将疗效与 增加NAD+水平。这项工作将推动NR治疗CIPN的大型III期研究， 发现一种新的药物疗法，以满足肿瘤学中重大未满足的需求。这些发现具有很大的 有潜力通过一种治疗来改变肿瘤学的实践，从而在肿瘤学方面产生有意义的改善。 患者的生活质量和完成最佳化疗治疗方案的能力。