Promoting Response to IMmunotherapy by Exercise in Patients With Advanced Renal Cell Carcinoma (PRIMER)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Oncology
• Intervention / Treatment: Behavioral: HIIT

Detailed Description

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.

Physical fitness tests, questionnaires and Fitbit to monitor physical activity will be used to evaluate functional and patient-reported outcomes.

This pilot study will provide important information on the feasibility of exercise during immunotherapy and generate preliminary data on potential immunological effects. These findings will inform the design of future larger trials aimed to optimize supportive care and improve treatment outcomes for patients with advanced RCC.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laurien Buffart, PhD; Phone Number: +31 24 3667310; Email: laurien.buffart@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Arnhem, Gelderland, Netherlands
      • Rijnstate
    • Nijmegen, Gelderland, Netherlands
      • RadboudUMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years.
• Diagnosed with advanced RCC with indication for standard-of-care dual ICI treatment.
• Able and willing to give written informed consent.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Intensity Interval Training (HIIT); High intensity aerobic interval training during dual immunotherapy	Behavioral: HIIT; The intervention group will be offered a supervised exercise program consisting of two 60-minute sessions per week, including continuous aerobic exercise and HIIT. Sessions will be supervised by physiotherapists specialized in oncology, and the training load will be tailored to a patient's individual fitness levels throughout the intervention. Following a short warm-up, participants will perform repeated high-intensity cycling intervals targeting 85-95% of their estimated peak heart rate corresponding to a Borg Rating of Perceived Exertion (RPE) 16-18), interspersed with periods of active recovery at light intensity. The HIIT component will be followed by moderate-intensity aerobic exercise at approximately 70% of the estimated heart rate (Borg RPE 13-14), and a cool-down period. In addition, participants will be asked to be physically active for at least 30 minutes at moderate intensity, in accordance with the American College of Sports Medicine (ACSM) guidelines.
No Intervention: Usual care control (UC); The control group will receive usual care and will be receive a folder about physical activity recommendations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participation rate	Calculated by the proportion of eligible patients that participate. An accrual rate lower than 20% will be defined as not feasible.	Study enrolment period (approximately 24 months)
Exercise intervention adherence	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	12 weeks (during intervention period)
Immune-related and exercise-related adverse events	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.	24 weeks (during intervention period of 12 weeks, and 12 weeks post intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition	Bioelectrical Impedance Analysis (BIA), Length (cm), Body weight (kg), Muscle mass (kg), Body fat percentage (%). Weight and height will be combined to report BMI in kg/m²	12 weeks (Baseline, post-intervention)
Estimated aerobic fitness	Steep ramp test	12 weeks (Baseline, post-intervention)
Lower body muscle function	Lower body muscle function will be assessed using a sit-to-stand test	12 weeks (Baseline, post-intervention)
Physical activity	Modified Godin Leisure-Time Exercise Questionnaire, Fitbit continuously	12 weeks (Baseline, post-intervention)
Health-related quality of life (HRQoL)	European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire	12 weeks (Baseline, post-intervention)
Fatigue	European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Fatigue Module (EORTC QLQ FA12) questionnaire	12 weeks (Baseline, post-intervention)
Anxiety and depression	Hospital Anxiety and Depression Scale (HADS) questionnaire	12 weeks (Baseline, post-intervention)
Sleep	Pittsburgh Sleep Quality Index (PSQI) questionnaire	12 weeks (Baseline, post-intervention)
Diet	World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations Questionnaire	12 weeks (Baseline, post-intervention)
ctDNA	Venous blood sampling, concetration ctDNA (ng/mL) next-generation sequencing	12 weeks (baseline, 6 weeks, and post-intervention)
Immune cell phenotype and function, and inflammatory markers	Venous blood sampling and flow cytometry to determine frequency (%) of circulating immune cells, functional characteristics of circulating immune cells will be determined using functional assays, inflammatory marker concentrations will measured (pg/mL or ng/mL).	12 weeks (baseline, 6 weeks, and post-intervention)
Gut microbiome composition	Taxonomic features and alpha and beta diversity via 16S rRNA marker gene sequencing of feces samples	12 weeks (baseline, 6 weeks, and post-intervention)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Laurien M Buffart, PhD, Radboud University Medical Center; Principal Investigator: Sasja F Mulder, MD, PhD, Radboud University Medical Center; Principal Investigator: Theo van Voorthuizen, MD, Rijnstate

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: June 17, 2026
• First Submitted That Met QC Criteria: June 25, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Exercise; randomized controlled trial; immunotherapy; Oncology; immune function; Renal cell carcinoma; immune-related adverse events
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Behavior; Neoplasms; Carcinoma, Renal Cell; Motor Activity
• Other Study ID Numbers: NL-011443 (Other Identifier: Medical Ethical Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared via the POLARIS consortium see PROSPERO registry CRD42013003805 or paper: Buffart et al. Systematic Reviews 2013; 2: 75.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No