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

项目总结/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抗性。高效低成本 迫切需要能够以最小毒性长期给药的策略。结构好氧 运动疗法（下文称为运动）是这样一种候选方法。然而，大多数运动肿瘤学 到目前为止，已经对早期癌症进行了研究，以测试运动对症状控制的影响 结果（例如，疲劳、疼痛）。要发展运动作为抗癌策略，需要进行早期研究 以确定适当的运动剂量进行进一步的测试-这是一个强制性的先决条件， 发展，但在运动作为一种治疗策略的发展中很大程度上被忽视了。整体 这项资助的目的是确定HR阳性MBC患者的最佳运动剂量。之前 观察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药物的下一步发展 干预是确定随机对照试验（RCT）中测试的最佳剂量。我们组最近 报告了一项先锋临床试验（R21 CA 133186），首次显示了 具有良好体能状态的MBC患者中保守运动处方的有希望获益 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 在1a期剂量探索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，40例绝经后 接受HR阳性MBC一线治疗的女性将被分配到五种运动剂量之一， 包括每周3至5天的监督个性化跑步机步行，50%至85%的运动能力， 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MFD 低于MFD。主要终点是耐受性。次要终点是生物学和临床 活动将通过肿瘤负荷的变化评估生物活性，通过循环肿瘤DNA定量 在连续获得的液体活组织检查中的ctDNA。将通过放射学肿瘤缓解评估临床活性， 无进展生存率和生活质量指标。我们假设，一个可耐受的运动量将是 该剂量将具有抗肿瘤活性，其特征在于肿瘤负荷（ctDNA）降低 以及与历史数据相比临床反应的改善。这一贡献意义重大，因为它 将告知在确定性RCT中进行测试的推荐2期运动剂量。这项建议是 创新，因为它采用了严格的标准，从肿瘤药物开发，并纳入新的液体 活组织检查技术（例如，ctDNA），从而为运动肿瘤学研究和实践设定了新的标准。

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.