TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol (TACTIC) Trial

TrAstuzumab 心肌病卡维地洛治疗干预 (TACTIC) 试验

基本信息

批准号：
10579872
负责人：
Joerg Herrmann
金额：
$ 79.84万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10579872
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 Development Drops Epidermal Growth Factor Receptor Genetic Genetic Predisposition to Disease Heart Abnormalities Heart Injuries Heart failure Human Incidence Injury 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 Records Recovery Recovery of Function Risk Role Specific qualifier value Symptoms Testing Therapeutic Intervention Time Trastuzumab Troponin active method cardioprotection cardiovascular risk factor carvedilol clinical care cohort experience genetic variant heart function high risk improved malignant breast neoplasm mortality patient population randomized, clinical trials response side effect targeted treatment therapy duration treatment arm treatment duration treatment response ultrasound

项目摘要

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.

项目概要曲妥珠单抗是一种针对人表皮生长因子 (EGF) 受体 2 (HER-2) 的单克隆抗体，然而，它彻底改变了 HER-2 阳性乳腺癌的治疗，但其心脏毒性的副作用限制了治疗。我们发现 40% 的患者在治疗期间出现左心室射血分数 (LVEF) 下降 >10% 曲妥珠单抗治疗后，4% 的患者出现心力衰竭 (HF)，其中 25-50% 的患者 LVEF 并未完全下降。即使采用心血管治疗也是可逆的，遗传因素是导致心脏脆弱性的最佳因素。心血管管理策略尚不清楚。存在曲妥珠单抗引起的心脏毒性风险的患者。当前申请的目标是评估使用卡维地洛的心脏保护方法的治疗意图我们的中心假设是曲妥珠单抗用于治疗 HER-2 阳性乳腺癌。方法（在曲妥珠单抗治疗之前开始使用 β 受体阻滞剂卡维地洛进行心血管治疗），或反应性预防方法（针对心脏功能障碍的早期亚临床症状开始心血管治疗/ 损伤，即心肌肌钙蛋白升高或异常整体纵向应变（GLS））将减少心脏毒性与标准的“观望”方法（一旦发生心脏毒性就开卡维地洛）相比。我们还发现，卡维地洛在曲妥珠单抗治疗之外的延长治疗效果更佳。结果，药物基因组学可以预测对心血管治疗无反应的心脏毒性这项临床试验将测试这些假设，涉及 450 名成年乳腺癌患者。治疗性曲妥珠单抗治疗，随机分为先发制人、反应性或参考治疗方法。本研究涉及三个具体研究目标：目标 1：比较 a) LVEF ≥ 50% 或 LVEF 无症状下降 > 10% 的发生率 LVEF 下降至最低点 <50% 的患者≥5%（主要目标#1），并且 b) 可逆 LVEF 下降至采用先发制人、反应性和“观望”的方法，在基线的 5% 以内（次要目标 #1）乳腺癌患者在曲妥珠单抗辅助治疗过程中开始使用卡维地洛这一目标旨在解决这一问题。启动曲妥珠单抗治疗心脏保护工作的问题。目标 2：比较曲妥珠单抗治疗完成后 1 年内 LVEF 的增量变化卡维地洛的心脏保护方法限制了曲妥珠单抗治疗的持续时间或延长了 1 此目标解决了曲妥珠单抗治疗的心脏保护作用的持续时间问题。目标 3：测试预定义的遗传变异与术中和术后 GLS 和 LVEF 变化之间的关联曲妥珠单抗治疗，针对治疗组进行调整此目的是确定预测曲妥珠单抗的基因变异。一般心脏毒性以及缺乏反应（一级预防 LVEF 下降或二级改善 LVEF）至卡维地洛。该试验的完成将指导临床护理寻求最佳的心脏保护管理策略（“策略”）接受曲妥珠单抗治疗的乳腺癌患者的疗效、开始时间和持续时间用β受体阻滞剂卡维地洛治疗。