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

基本信息

批准号：
10609405
负责人：
Neil Mukund Iyengar
金额：
$ 65.78万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2019-04-03 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609405
关键词：
Adherence Adverse event Aerobic Exercise Animals Antiestrogen Therapy Biological Breast Cancer Patient CDK4 gene Cancer Intervention Chronic Clinical Clinical Trials Combined Modality Therapy Common Terminology Criteria for Adverse Events Data Development Dose Emulsions Enrollment Exercise Exercise Test Exercise Therapy Fatigue Grant Image Imaging Techniques Malignant Neoplasms Measures Metastatic breast cancer Molecular Observational Study Oncology Outcome Pain Pathway interactions Patient-Focused Outcomes Patients Performance Status Phase Phase Ia Trial Phase Ia/Ib Trial Pilot Projects Plasma Polymerase Chain Reaction Postmenopause Prediction of Response to Therapy Prognosis Progression-Free Survivals Quality of life Randomized, Controlled Trials Recommendation Regimen Reporting Research Research Design Resistance Safety Signal Transduction Solid Structure Symptoms Techniques Technology Testing Time Toxic effect Tumor Burden Walking Woman Work anti-cancer antitumor effect appropriate dose cancer therapy circulating DNA clinical subtypes cohort cost drug development exercise capacity exercise prescription exercise training hormone receptor-positive hormone therapy improved improved outcome inhibitor innovation instrument liquid biopsy malignant breast neoplasm mouse model mutant novel pharmacologic phase III trial post intervention pre-clinical primary endpoint public health relevance radiological imaging response safety and feasibility secondary endpoint standard of care therapy resistant treadmill treatment strategy tumor tumor DNA virtual

项目摘要

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，并且几乎都会产生治疗耐药性。有效但成本低。迫切需要可以长期进行且毒性最小的策略。运动疗法（以下简称运动）就是这样一种候选方法，但是大多数运动肿瘤学。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。此项资助的目的是确定 HR 阳性 MBC 患者的最佳运动剂量。观察和临床前证据提供了有希望的关联假设生成数据运动与改善预后之间的关系是运动抗癌发展的下一步。干预措施的目的是确定我们小组最近在随机对照试验（RCT）中进行测试的最佳剂量。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具有良好体能状态的 MBC 患者有希望带来的益处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 In Aim 1, 40 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% 目标 2 中具有里程碑意义的 24 周，40 名绝经后 MBC 患者将接受运动或一剂 MFD。主要终点是耐受性，次要终点是生物学和临床。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）在连续获得的液体活检中的临床活性将通过放射学肿瘤反应进行评估，我们勇敢地说，可忍受的运动量将是无进展生存期和生活质量的衡量标准。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，因为它将告知最终随机对照试验中推荐的第 2 阶段运动剂量。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。