Phase 1a/1b Trial of Exercise Treatment in Hormone Receptor-Positive Metastatic Breast Cancer

激素受体阳性转移性乳腺癌运动治疗 1a/1b 期试验

• 批准号: 9756494
• 负责人: Neil Mukund Iyengar
• 金额: $ 69.44万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756494
• 关键词: Address; Adherence; Adverse event; Aerobic Exercise; Animals; Antiestrogen Therapy; Biological; Breast Cancer Patient; CDK4 gene; Cancer Intervention; Chronic; Clinical; Clinical Trials; Common Terminology Criteria for Adverse Events; Data; Development; Diagnostic radiologic examination; Dose; Emulsions; Enrollment; Exercise; Exercise Therapy; Exercise stress test; Fatigue; Grant; Image; Imaging Techniques; Malignant Neoplasms; Measures; Metastatic breast cancer; Molecular; Observational Study; Outcome; Pain; Pathway interactions; Patient-Focused Outcomes; Patients; Performance Status; Pharmacology; Phase; Phase III Clinical Trials; Pilot Projects; Plasma; Polymerase Chain Reaction; Postmenopause; Prediction of Response to Therapy; Progression-Free Survivals; Quality of life; Randomized; Regimen; Reporting; Research; Research Design; Resistance; Safety; Signal Transduction; Solid; Structure; Supervision; Symptoms; Techniques; Technology; Testing; Time; Toxic effect; Tumor Burden; Walking; Woman; Work; anti-cancer; antitumor effect; appropriate dose; base; breast cancer progression; cancer therapy; circulating DNA; clinical subtypes; cohort; control trial; cost; drug development; exercise capacity; exercise prescription; exercise training; hormone receptor-positive; hormone therapy; improved; improved outcome; inhibitor/antagonist; innovation; instrument; liquid biopsy; malignant breast neoplasm; mouse model; mutant; novel; oncology; outcome forecast; pre-clinical; preclinical study; primary endpoint; public health relevance; response; safety and feasibility; secondary endpoint; standard of care; therapy resistant; treadmill; treatment strategy; tumor; tumor DNA; virtual

PROJECT SUMMARY/ABSTRACT Nearly half of patients receiving first line therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) do not respond to treatment, and virtually all develop treatment resistance. Efficacious but low cost strategies that can be chronically administered with minimal toxicity are urgently required. Structured aerobic exercise therapy (hereafter exercise) is one such candidate approach. However, most exercise-oncology studies to date have been conducted in early-stage cancers to test the impact of exercise on symptom control outcomes (e.g., fatigue, pain). To develop exercise as an anticancer strategy, early phase studies are required to determine the appropriate exercise dose for further testing – this is a mandatory prerequisite in drug development but one largely ignored in the development of exercise as a treatment strategy. The overall objective of this grant is to identify the optimal dose of exercise in patients with HR-positive MBC. Prior observational and preclinical evidence provide promising hypothesis-generating data of an association between exercise and improved prognosis. The next step in the development of exercise as an anti-cancer intervention is to identify the optimal dose for testing in randomized control trials (RCTs). Our group recently reported a vanguard clinical trial (R21 CA133186) showing, for the first time, the feasibility, safety, and promising benefit of a conservative exercise prescription in MBC patients with good performance status receiving 1st or 2nd-line therapy. Based on this strong scientific rationale, our specific aims are (1) to identify the maximum feasible dose (MFD) of exercise in a phase 1a dose-finding study, and (2) to further assess tolerability and biological / clinical activity in a phase 1b dose-expansion cohort. In Aim 1, 40 postmenopausal women receiving first-line therapy for HR-positive MBC will be allocated to one of five exercise doses which will consist of supervised individualized treadmill walking 3 to 5 days/week, at 50% to 85% exercise capacity for landmark 24 weeks. In Aim 2, 40 postmenopausal MBC patients will receive the MFD of exercise or one dose level below the MFD. The primary endpoint is tolerability. Secondary endpoints are biological and clinical activity. Biological activity will be assessed by change in tumor burden, quantified by circulating tumor DNA (ctDNA) in serially obtained liquid biopsies. Clinical activity will be assessed by radiographic tumor response, progression free survival, and quality of life measures. We hypothesize that a tolerable dose of exercise will be identified and that this dose will have antitumor activity characterized by reductions in tumor burden (ctDNA) and improvements in clinical response compared to historical data. This contribution is significant because it will inform the recommended phase 2 dose of exercise for testing in definitive RCTs. This proposal is innovative because it adapts rigorous standards from oncology drug development and incorporates novel liquid biopsy technology (e.g., ctDNA), thereby setting a new standard for exercise oncology research and practice.

项目摘要/摘要 近一半接受激素受体(HR)阳性转移性乳腺癌一线治疗的患者 (MBC)对治疗没有反应，几乎所有人都产生了治疗耐药性。见效快，成本低 迫切需要能够在毒性最小的情况下长期实施的战略。结构好氧 运动疗法(以下简称运动疗法)就是这样一种候选方法。然而，大多数运动肿瘤学 到目前为止，已经在早期癌症中进行了研究，以测试锻炼对症状控制的影响。 结果(例如，疲劳、疼痛)。为了将运动作为一种抗癌策略，需要进行早期研究 为进一步测试确定适当的运动量-这是药物的强制性先决条件 发展，但一个很大程度上被忽视的发展，把运动作为一种治疗策略。整体而言 这笔赠款的目的是确定HR阳性MBC患者的最佳运动剂量。之前 观察性证据和临床前证据提供了有希望的假设生成数据。 运动和改善预后之间的关系。运动作为抗癌发展的下一步 干预措施是在随机对照试验(RCT)中确定试验的最佳剂量。我们的小组最近 报道了一项先锋临床试验(R21 CA133186)，首次显示了其可行性、安全性和 运动状态良好的MBC患者采用保守运动处方有望获益 接受一线或二线治疗。基于这一强有力的科学依据，我们的具体目标是：(1)确定 1a阶段剂量发现研究中的运动最大可行剂量(MFD)，以及(2)进一步评估 1b期剂量扩展队列中的耐受性和生物学/临床活性。在目标1中，绝经后40 接受HR阳性MBC一线治疗的女性将被分配到五种运动量中的一种，这将 由有监督的个性化跑步机组成，每周步行3至5天，运动能力为50%至85% 里程碑式的24周。在目标2中，40名绝经后MBC患者将接受运动或一剂的MFD。 低于MFD的级别。主要终点是耐受性。次要终点是生物学和临床终点。 活动。生物活性将通过肿瘤负荷的变化来评估，通过循环的肿瘤DNA来量化 (CtDNA)在连续获得的液体活检中。临床活动性将通过放射学肿瘤反应来评估， 无进展生存期和生活质量指标。我们假设可以承受的运动量将是 该剂量将具有抗肿瘤活性，其特征是降低肿瘤负担(Ctdna)。 与历史数据相比，临床反应有所改善。这一贡献意义重大，因为它 将通知推荐的第二阶段运动剂量，以便在最终的随机对照试验中进行测试。这项建议是 创新，因为它适应了肿瘤学药物开发的严格标准，并加入了新的液体 活组织检查技术(例如，ctDNA)，从而为运动肿瘤学的研究和实践设定了新的标准。