Determining Mechanisms and Measures for the Design of Chemotherapy-Induced Peripheral Neuropathy Clinical Trials in Adolescents and Young Adults with Cancer

确定青少年和年轻癌症患者化疗引起的周围神经病变临床试验设计的机制和措施

• 批准号: 10155582
• 负责人: Robert James Knoerl
• 金额: $ 11.36万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-04 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155582
• 关键词: Address; Adolescent and Young Adult; Adult; Algorithms; Biological; Biological Markers; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Coenzymes; Common Terminology Criteria for Adverse Events; Complication; Dana-Farber Cancer Institute; Development; Development Plans; Dinucleoside Phosphates; Dose; Dose-Limiting; Environment; Extramural Activities; Functional disorder; Funding; Future; Genes; Genomics; Genotype; Goals; Hand; Individual; Intervention; Knowledge; Laboratories; Longitudinal Studies; Malignant Neoplasms; Measurement; Measures; Metabolic; Michigan; Microtubules; Mission; National Institute of Nursing Research; Neurons; Neuropathy; Nicotinamide adenine dinucleotide; Numbness; Outcome; Outcome Measure; Outcomes Research; Paclitaxel; Pain; Patient Outcomes Assessments; Physical Function; Physiological; Postdoctoral Fellow; Prevention; Property; Psychometrics; Public Health; Quality of life; Questionnaires; Randomized Controlled Trials; Reporting; Research; Research Personnel; Research Training; Resources; Risk; Sample Size; Self Management; Serum; Severities; Stratification; Symptoms; Testing; Time; Toxic effect; Training; Translational Research; Universities; Vincristine; Work; Yoga; axonal degeneration; axonopathy; base; cancer therapy; career; career development; chemotherapy; clinical development; design; efficacy study; efficacy testing; experience; foot; functional disability; high risk; improved; innovation; leukemia/lymphoma; malignant breast neoplasm; metabolomics; mortality; mortality risk; negative affect; neurotoxic; nicotinamide-beta-riboside; preclinical study; preservation; prevent; prevention clinical trial; preventive intervention; skills; symptom management; symptom science; treatment response; treatment strategy; trial design; young adult

Project Summary Long-TermCareer Goal: Dr. Knoerl’s long-term career goal is to decrease suffering and maximize chemotherapy dosing in adolescents and young adults (AYAs) by identifying translational treatment strategies for chemotherapy-induced peripheral neuropathy (CIPN). Clinical Problem: CIPN (e.g., numbness/tingling in hands/feet) is a common complication of vincristine/paclitaxel chemotherapy that is associated with reductions in chemotherapy dosing, thereby increasing the risk of mortality. Yet, there are no recommended treatments for CIPN prevention and little is known about CIPN in AYAs to guide the development of clinical trials. Candidate Background: Dr. Knoerl trained at the University of Michigan and gained expertise leading CIPN management trials by conducting a randomized controlled trial to test the efficacy of an online self- management intervention for chronic painful CIPN. Dr. Knoerl is currently a postdoctoral fellow at Dana-Farber Cancer Institute (DFCI) and has earned internal funding to study the efficacy of a clinician decision support algorithm to improve CIPN assessment; and extramural funding to explore the impact of yoga for CIPN. Career Development Plan: The conduct of this K23 proposal will further advance the candidate to his goal of becoming an independent, translational symptom science investigator by providing him with specific training in 1) the measurement and analysis of metabolic and genomic intermediaries, 2) mechanisms of CIPN development, and 3) the design, measurement, and analysis of patient-reported outcomes in a clinical trial. DFCI is an optimal environment for training as the candidate will have access to experts, coursework, and resources aligned with the research and training aims. Specific Aims: The overall objective of this longitudinal study is to determine factors crucial to the design of CIPN prevention clinical trials for AYAs with cancer. The primary aim is to determine the association between serum nicotinamide riboside dinucleotide (NAD+) levels and CIPN severity and associated functional interference. Secondary aims are to 1) evaluate the association between the high risk CEP72 (TT at rs924607) genotype and CIPN severity and associated functional impairment 2) examine the psychometric properties of the Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). Expected Outcomes: Establishing NAD+ as a physiological influencing factor of CIPN development will direct future work towards the testing of interventions to boost NAD+ for CIPN prevention. The identification of CEP72 as a biomarker of CIPN will increase statistical power and allow for the stratification of AYAs examine treatment response in future trials. Determining the psychometric properties of the QLQ-CIPN20 will aid in the identification of efficacious CIPN interventions in AYAs.

项目概要 长期职业目标：Knoerl 博士的长期职业目标是减少痛苦并最大化 通过确定转化治疗策略来确定青少年和年轻人 (AYAs) 的化疗剂量 用于化疗引起的周围神经病变（CIPN）。 临床问题：CIPN（例如手/脚麻木/刺痛）是一种常见并发症 长春新碱/紫杉醇化疗与化疗剂量的减少相关，从而 增加死亡风险。然而，目前还没有预防 CIPN 的推荐治疗方法，而且目前也没有什么推荐的治疗方法。 了解 AYA 中的 CIPN，以指导临床试验的开展。 候选人背景：Knoerl 博士在密歇根大学接受培训，并获得了领导 CIPN 的专业知识 管理试验，通过进行随机对照试验来测试在线自我管理的有效性 慢性疼痛 CIPN 的管理干预。 Knoerl 博士目前是丹娜—法伯癌症研究所的博士后研究员 癌症研究所 (DFCI) 并已获得内部资金来研究临床医生决策支持的功效 改进 CIPN 评估的算法；以及校外资金来探索瑜伽对 CIPN 的影响。 职业发展计划：此 K23 提案的实施将进一步推动候选人实现其目标： 通过为他提供以下方面的具体培训，成为一名独立的转化症状科学研究者 1）代谢和基因组中间体的测量和分析，2）CIPN的机制 开发，3) 临床试验中患者报告结果的设计、测量和分析。 DFCI 是最佳的培训环境，因为候选人将能够接触专家、课程和资源 与研究和培训目标保持一致。 具体目标：这项纵向研究的总体目标是确定对设计的关键因素 针对患有癌症的 AYA 的 CIPN 预防临床试验。主要目的是确定之间的关联 血清烟酰胺核苷二核苷酸 (NAD+) 水平和 CIPN 严重程度及相关功能 干涉。次要目标是 1) 评估高风险 CEP72（TT 位于 rs924607）之间的关联 基因型和 CIPN 严重程度以及相关功能障碍 2) 检查心理测量特性 生活质量问卷-化疗引起的周围神经病变（QLQ-CIPN20）。 预期成果：将NAD+确立为CIPN发展的生理影响因素将指导 未来的工作是测试干预措施，以增强 NAD+ 预防 CIPN。鉴定 CEP72 作为 CIPN 的生物标志物将提高统计功效并允许对 AYA 检查进行分层 未来试验中的治疗反应。确定 QLQ-CIPN20 的心理测量特性将有助于 确定 AYA 中有效的 CIPN 干预措施。