TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol (TACTIC) Trial

TrAstuzumab 心肌病卡维地洛治疗干预 (TACTIC) 试验

• 批准号: 10357789
• 负责人: Joerg Herrmann
• 金额: $ 82.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357789
• 关键词: Address; Adjuvant; Adrenergic beta-Antagonists; Adult; Anthracycline; Biological Markers; Blood; Breast Cancer Patient; Breast Cancer Treatment; Cardiac; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Caring; Clinic; Clinical Trials; Data; Drops; ERBB2 gene; Epidermal Growth Factor Receptor; Genetic; Genetic Predisposition to Disease; Heart Abnormalities; Heart Injuries; Heart failure; Human; Incidence; Injury; Institutes; Intervention; Lead; Left Ventricular Ejection Fraction; Malignant Neoplasms; Measures; Monoclonal Antibodies; Myocardial dysfunction; Outcome; Outcome Measure; Patient-Focused Outcomes; Patients; Pharmacogenomics; Preventive; Primary Prevention; Prognosis; Publishing; Randomized; Randomized Clinical Trials; Records; Recovery; Recovery of Function; Risk; Role; Specific qualifier value; Symptoms; Testing; Therapeutic Intervention; Time; Trastuzumab; Troponin; active method; base; cardiogenesis; cardioprotection; cardiovascular risk factor; carvedilol; clinical care; cohort; experience; genetic variant; heart function; high risk; improved; malignant breast neoplasm; mortality; patient population; response; side effect; targeted treatment; therapy duration; treatment arm; treatment duration; treatment response; ultrasound

PROJECT SUMMARY Trastuzumab, a monoclonal directed against the human epidermal growth factor (EGF) receptor-2 (HER-2), revolutionized HER-2-positive breast cancer treatment, albeit, with the therapy-limiting side effect of cardiotoxicity. We found that 40% of patients experience a left ventricular ejection fraction (LVEF) decline >10% during trastuzumab therapy, and 4% develop heart failure (HF). In 25-50% of these cases, the LVEF decline is not fully reversible, even with cardiovascular therapy. Genetic contributors to cardiac vulnerability and the best cardiovascular management strategy are unknown. A critical need exists for cardio-preventive approaches in patients at risk of trastuzumab-induced cardiotoxicity. The current application’s objective is to evaluate cardio-protective approaches using carvedilol in curative-intent trastuzumab for HER-2-positive breast cancer. Our central hypotheses are that a pre-emptive preventive approach (cardiovascular therapy with the beta-blocker carvedilol started before trastuzumab therapy), or a reactive preventive approach (cardiovascular therapy started in response to early subclinical signs of cardiac dysfunction/ injury, i.e. cardiac troponin elevation or abnormal global longitudinal strain (GLS)) will reduce cardiotoxicity compared with a standard “wait-and-see” approach (carvedilol prescribed once cardiotoxicity has occured). We furthermore hypothesize that carvedilol extension beyond the active trastuzumab treatment leads to superior outcomes and that pharmacogenomics can predict cardiotoxicity non-responsive to cardiovascular therapy with carvedilol. This clinical trial will test these hypotheses, involving 450 adult breast cancer patients beginning a year of curative-intent trastuzumab therapy, randomized to either a preemptive, a reactive, or reference care approach. This study addresses three specific study aims: Aim 1: To compare the incidence of a) HF or asymptomatic decline in LVEF by >10% in those with LVEF ≥50% or ≥5% in those with LVEF decrease to a nadir of <50% (lead primary aim #1), and b) reversible LVEF decline to within 5% of baseline (secondary primary aim #1) with a pre-emptive, reactive, and “wait-and-see” approach of carvedilol initiation in breast cancer patients over the course of adjuvant trastuzumab therapy. This aim addresses the question of initiation of cardioprotective efforts for trastuzumab therapy. Aim 2: To compare the delta change in LVEF from completion to 1 year post-completion of trastuzumab therapy between a cardioprotective approach with carvedilol confined the duration of trastuzumab therapy or extended for 1 year thereafter. This aim addresses the question of duration of cardioprotective efforts for trastuzumab therapy. Aim 3: To test the association of predefined genetic variants with change in GLS and LVEF during and after trastuzumab therapy, adjusted for treatment arm. This aim is to identify genetic variants that predict trastuzumab cardiotoxicity in general as well as lack of response (primary prevention of drop in LVEF or secondary improvement of LVEF) to carvedilol. This trial’s completion will guide clinical care in seeking the best management strategy (“tactic”) for cardio-protection in breast cancer patients undergoing trastuzumab therapy in terms of efficacy, time of initiation, and duration of treatment with the beta-blocker carvedilol.

项目摘要 曲妥珠单抗，一种针对人表皮生长因子（EGF）受体-2（HER-2）的单克隆人 革命性的HER-2阳性乳腺癌治疗，尽管是心脏毒性的限制性副作用。 我们发现，有40％的患者经历了左心室射血分数（LVEF）下降> 10％ 曲妥珠单抗治疗，4％发展心力衰竭（HF）。在这些情况中，有25-50％的LVEF下降尚未完全 即使进行心血管疗法，也可逆。心脏脆弱性的遗传因素和最佳 心血管管理策略尚不清楚。对心脏预防方法的关键需求 曲妥珠单抗引起的心脏毒性的风险。 当前的应用程序的目标是在现代使用卡维迪尔评估心脏保护方法 曲妥珠单抗Her-2阳性乳腺癌。我们的中心假设是先发制人的预防性 进近（用β受体阻滞剂卡维地醇的心血管疗法开始之前，曲妥珠单抗治疗开始）或反应性 预防方法（心血管疗法开始，以应对心脏功能障碍的早期亚临床迹象/ 损伤，即心脏肌钙蛋白高程或异常全球纵向应变（GLS）将降低心脏毒性 与标准的“等待方式”方法相比（发生心脏毒性一旦出现了卡维迪尔的规定）。 我们进一步假设，超出活性曲妥珠单抗治疗以外的卡维地醇延伸导致优越 结果和药物基因组学可以预测心脏毒性对心血管疗法无反应性 卡维洛尔。该临床试验将检验这些假设，涉及450名成年乳腺癌患者开始一年 治愈性曲妥珠单抗治疗，随机分为先发制人，反应性或参考方法。 这项研究针对三个特定的研究目的： 目的1：比较LVEF≥50％或 LVEF患者的≥5％降低到<50％的Nadir（主要目标＃1），b）可逆LVEF下降到 在基线的5％之内（次要初级目标＃1）以前，具有先验性，反应性和“等待”方法 在可调节的曲妥珠单抗治疗过程中，乳腺癌患者的carvedilol启动。这个目的解决了 曲妥珠单抗治疗的心脏保护努力的问题。 目标2：比较曲妥珠单抗治疗后1年的LVEF的三角洲变化 在用卡维地（Carvedilol）限制曲妥珠单抗治疗持续时间或延伸1的心脏保护方法之间 此后一年。该目的解决了曲妥珠单抗治疗的心脏保护工作持续时间的问题。 AIM 3：测试预定义遗传变异与GLS和LVEF的变化的关联期间和之后 曲妥珠单抗治疗，调整为治疗臂。这个目的是识别预测曲妥珠单抗的遗传变异 心脏毒性一般和缺乏反应（主要预防LVEF或次要改善 lvef）到卡维洛尔。 该试验的完成将指导临床护理寻求最佳管理策略（“战术”）以进行心脏保护 在接受曲妥珠单抗治疗的乳腺癌患者中，就效率，开始时间和持续时间而言 用β受体阻滞剂卡维醇治疗。