Promoting Response to IMmunotherapy by Exercise in Patients With Advanced Renal Cell Carcinoma
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Participation rate
研究概览
简要总结
The primary aim of this study is to evaluate the feasibility of a supervised high intensity interval training (HIIT) program during first-line dual immune checkpoint inhibitor (ICI) therapy (nivolumab plus ipilimumab) in patients with advanced renal cell carcinoma (RCC). The second aim is to generate preliminary data on the effects of exercise on the immune cell phenotype and function, gut microbiota composition, physical fitness, patient-reported outcomes and clinical outcomes.
This is a two-arm randomized controlled pilot trial in which 30 patients with advanced RCC scheduled to receive first-line nivolumab plus ipilimumab will be randomized in 1:1 ratio to an exercise intervention group or usual care group. The exercise intervention consists of two 60-minute supervised HIIT sessions per week, delivered by oncology-trained physiotherapists and one additional home-based moderate-intensity aerobic exercise sessions per week. The intervention starts with the first cycle of immunotherapy and continues for four treatment cycles. Participants in both groups will receive usual care and general exercise guidelines. Measurements include blood and stool sampling for microbiome and immune parameters analysis, physical fitness assessments, physical fitness monitoring, body composition measurements, and patient-reported outcomes related to quality of life, fatigue, depression, sleep and diet.
详细描述
There is strong evidence from randomized controlled trials that exercise during cancer treatment can maintain physical fitness, limit fatigue, and enhance health-related quality of life (HRQoL). Some studies also showed that exercise may help patients to better tolerate their treatment. However, most exercise trials have been conducted in patients receiving chemotherapy or radiotherapy, and little is known about the feasibility or effects of exercise during immunotherapy, particularly in patients with advanced RCC.
First-line treatment for patients with advanced RCC often consists of dual ICI treatment with nivolumab plus ipilimumab. While this combination has shown to improve survival, a substantial proportion of patients do not respond, and approximately 44% experience any grade immune-related adverse events. Tumor hypoxia, an immunosuppressive tumor microenvironment, and insufficient infiltration of cytotoxic immune cells are key factors believed to contribute to treatment resistance.
Preclinical studies in mice have shown that aerobic exercise can positively influence the tumor microenvironment through reduced tumor hypoxia, enhanced tumor perfusion, and increased activity and infiltration of cytotoxic immune cells such as CD8+ T cells and natural killer (NK) cells, while reducing immunosuppressive cell populations. In addition, preclinical studies in mice suggested that exercise-induced changes in the gut microbiome can further support immune activation and improve responses to immunotherapy. Despite this promising biological rationale, no clinical studies have evaluated whether supervised exercise is feasible or beneficial in patients with advanced RCC.
The primary objective of this pilot randomized controlled trial is to evaluate the feasibility of a supervised exercise program during first-line dual ICI therapy in patients with advanced RCC. Secondary objectives are to explore the preliminary effects of exercise on immune phenotype and function, inflammatory markers, circulating tumor (ct)DNA, gut microbiome composition, body composition, aerobic fitness, muscle function, physical activity, and patient reported outcomes including HRQoL, fatigue, anxiety, depression, sleep, and diet. In addition, changes in immune function, gut microbiome composition and clinical outcomes will also be explored.
This study is a two-arm randomized controlled trial including 30 adult patients with advanced RCC. Participants will be randomized to the intervention arm that receives a supervised HIIT program in addition to usual care or to a usual care control arm. The intervention consists of two supervised 60-minute HIIT-exercise sessions per week, delivered by oncology trained physiotherapists, combined with one additional home-based moderate intensity exercise session of at least 30 min per week. The intervention starts with the first cycle of immunotherapy and continues for four treatment cycles. Blood and stool samples will be collected at baseline and at 6 weeks and 12 weeks during treatment to assess immune and microbiome changes. In addition, in participants allocated to the exercise intervention group, to evaluate the acute effects of exercise on the immune response, blood samples will be collected immediately before and after a supervised exercise session.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years.
- •Diagnosed with advanced RCC with indication for standard-of-care dual ICI treatment.
- •Able and willing to give written informed consent.
排除标准
- •Life expectancy <6 months.
- •Unable to perform basic activities of daily living such as walking.
- •Presence of cognitive impairment or severe emotional instability (e.g. schizophrenia, Alzheimer's disease, alcohol addiction), at the discretion of the investigator.
- •Presence of other disabling comorbidities that may interfere with the ability to perform physical exercise (e.g., heart failure, chronic obstructive pulmonary disease (COPD, GOLD stage 3 or 4), orthopaedic conditions, or neurological disorders such as hernia, paresis, amputation or active rheumatoid arthritis), at the discretion of the investigator.
- •Current participation in structured vigorous aerobic and/or resistance exercise ≥ 2 times per week at a level comparable to the intervention
研究组 & 干预措施
High Intensity Interval Training (HIIT)
High intensity aerobic interval training during dual immunotherapy
干预措施: HIIT (Behavioral)
Usual care control (UC)
The control group will receive usual care and will be receive a folder about physical activity recommendations.
结局指标
主要结局
Participation rate
时间窗: Study enrolment period (approximately 24 months)
Calculated by the proportion of eligible patients that participate. An accrual rate lower than 20% will be defined as not feasible.
Exercise intervention adherence
时间窗: 12 weeks (during intervention period)
Adherence will be assesed by attendance and exercise relative dose intensity (ExRDI). Attendence will be assessed by dividing the number of attended sessions by the number of prescribed sessions. ExRDI will be calculated as the percentage of the exercise intensity achieved during the performed sessions relative to the total prescribed exercise intensity expressed as a percentage. The information will be collected using questionnaires and exercise-logs registered by the physical therapists. These logs will be collected by the researcher
Immune-related and exercise-related adverse events
时间窗: 24 weeks (during intervention period of 12 weeks, and 12 weeks post intervention)
Immune related adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 based on medical records and the patient reported outcomes (PRO)-CTCAE completed by patients before each immunotherapy cycle and at 3-month follow up.
次要结局
- ctDNA(12 weeks (baseline, 6 weeks, and post-intervention))
- Body composition(12 weeks (Baseline, post-intervention))
- Estimated aerobic fitness(12 weeks (Baseline, post-intervention))
- Lower body muscle function(12 weeks (Baseline, post-intervention))
- Physical activity(12 weeks (Baseline, post-intervention))
- Health-related quality of life (HRQoL)(12 weeks (Baseline, post-intervention))
- Fatigue(12 weeks (Baseline, post-intervention))
- Anxiety and depression(12 weeks (Baseline, post-intervention))
- Sleep(12 weeks (Baseline, post-intervention))
- Diet(12 weeks (Baseline, post-intervention))
- Immune cell phenotype and function, and inflammatory markers(12 weeks (baseline, 6 weeks, and post-intervention))
- Gut microbiome composition(12 weeks (baseline, 6 weeks, and post-intervention))
- Gut microbiome composition(12 weeks (baseline and post-intervention))