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：
9906189
负责人：
Neil Mukund Iyengar
金额：
$ 69.43万
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/9906189
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 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 Pharmacology Phase Phase Ia Trial Phase Ia/Ib Trial 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 outcome forecast phase III trial 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

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.

项目摘要/摘要接受Horsene受体（HR）阳性转移性乳腺癌的第一线治疗的患者中，近一半（MBC）不要对治疗做出反应，几乎所有发育治疗的耐药性。有效但成本低迫切需要迫切需要以最小的毒性给予长期给药的策略。结构性有氧运动运动疗法（以后锻炼）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结果（例如疲劳，疼痛）。要发展运动作为抗癌策略，需要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发展，但在运动发展作为治疗策略时，很大程度上被忽略了。总体该赠款的目的是确定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假设生成的关联数据在运动和预后改善之间。作为反癌运动发展的下一步干预是确定在随机对照试验（RCT）中测试的最佳剂量。我们的小组最近报道了Vanguard临床试验（R21 CA133186）首次显示可行性，安全性和保守锻炼处方的有希望的好处在表现良好的MBC患者接受第一或第二线治疗。基于这种强大的科学原理，我们的具体目的是（1）确定在1A期剂量调查研究中的最大可行剂量（MFD），以及（2）进一步评估 1B剂量扩张队列中的耐受性和生物 /临床活性。在AIM 1，40个绝经后接受HR阳性MBC一线治疗的妇女将分配给五种运动剂量之一由受监督的个性化跑步机行走3至5天/周，以50％至85％的运动能力组成地标24周。在AIM 2中，40名绝经后MBC患者将接受运动或一剂低于MFD。主要终点是耐受性。次要终点是生物学和临床活动。生物学活性将通过肿瘤燃烧的变化来评估，并通过循环肿瘤DNA进行量化（ctDNA）在连续获得的液体活检中。临床活性将通过放射学肿瘤反应评估，无进展生存和生活质量措施。我们假设可以容忍的运动将是鉴定出来，该剂量的抗肿瘤活性为特征，其特征是肿瘤燃烧（CTDNA）的减少与历史数据相比，临床反应的改善。这项贡献很重要，因为它将告知建议在确定RCT中进行测试的2阶段练习。该提议是创新性是因为它适应了严格的肿瘤药物开发标准，并结合了新型液体活检技术（例如CTDNA），从而为运动肿瘤研究和实践设定了新的标准。