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.

项目概要/摘要 近一半的患者接受激素受体 (HR) 阳性转移性乳腺癌一线治疗 (MBC) 对治疗没有反应，并且几乎所有人都会产生治疗耐药性。有效但成本低 迫切需要能够以最小毒性长期给药的策略。结构化有氧运动 运动疗法（以下简称运动）就是这样一种候选方法。然而，大多数运动肿瘤学 迄今为止，已经在早期癌症中进行了研究，以测试运动对症状控制的影响 结果（例如疲劳、疼痛）。为了将运动作为一种抗癌策略，需要进行早期研究 确定适当的运动剂量以进行进一步测试——这是药物的强制性先决条件 但在将运动作为一种治疗策略的发展过程中，人们很大程度上忽视了这一点。整体 此项资助的目的是确定 HR 阳性 MBC 患者的最佳运动剂量。事先的 观察和临床前证据提供了有希望的关联假设生成数据 锻炼和改善预后之间的关系。运动作为抗癌药物的下一步发展 干预的目的是确定随机对照试验（RCT）中测试的最佳剂量。我们组最近 报道了一项先锋临床试验（R21 CA133186），首次显示了可行性、安全性和 保守运动处方对体能状态良好的 MBC 患者有希望获益 接受第一或第二线治疗。基于这一强有力的科学原理，我们的具体目标是 (1) 确定 1a 期剂量探索研究中运动的最大可行剂量 (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/临床活性。目标 1：40 岁绝经后 接受 HR 阳性 MBC 一线治疗的女性将被分配到五种运动剂量中的一种，这将 包括每周 3 至 5 天、在监督下的个性化跑步机步行，运动能力为 50% 至 85% 具有里程碑意义的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 的水平。主要终点是耐受性。次要终点是生物学和临床 活动。生物活性将通过肿瘤负荷的变化进行评估，并通过循环肿瘤 DNA 进行量化 （ctDNA）连续获得的液体活检。临床活性将通过放射学肿瘤反应进行评估， 无进展生存期和生活质量指标。我们假设可耐受的运动量是 已确定，该剂量将具有抗肿瘤活性，其特点是减少肿瘤负荷（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 将告知在最终随机对照试验中进行测试时推荐的第 2 阶段运动剂量。这个提议是 创新是因为它采用了肿瘤药物开发的严格标准并采用了新型液体 活检技术（例如 ctDNA），从而为运动肿瘤学研究和实践设立了新标准。