Clinical trial NCT06672120: Exercise in Triple- Negative Breast Cancer
Official title: Exercise in Regional Breast Cancer With Neoadjuvant Anthracycline- Based Chemotherapy and Immunotherapy With Checkpoint-Inhibition
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cancer, Breast
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
First posted: 2024-11-04
Enrollment: 120
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients diagnosed with TNBC and scheduled for immuno-chemotherapy will be randomized (1:1) into an intervention group receiving combined endurance and resistance training and a control group receiving standard exercise recommendations.
Primary purpose: SUPPORTIVE_CARE

Brief summary: This is a prospective, randomized, controlled mono-center study investigating the effects of a combined, supervised aerobic exercise and resistance training in female patients with newly diagnosed, therapy-naive triple-negative breast cancer (TNBC, stage I-III) between 18 and 50 years of age scheduled for anthracycline-based chemotherapy and immunotherapy with checkpoint inhibitors. All patients will receive smart watches for rhythm monitoring.

Patients will be randomized (1:1) into a control group, receiving 24 weeks of standard exercise recommendations during neoadjuvant therapy, and an intervention group receiving 24 weeks of home-based, video-supervised exercise training consisting of endurance and resistance training. The primary endpoint is the change of peak oxygen consumption (VO2peak) between baseline and 24 weeks in the groups. Secondary endpoints include changes of physical function (short physical performance battery, SPPB), as well as cardiac biomarkers, quality of life, and changes of strength of the upper and lower body between baseline and 24 weeks. In addition, variables of cardiopulmonary exercise testing (CPET), resting and stress echocardiography, and burden of atrial fibrillation (AF) will be assessed. All changes in variables will be analyzed from baseline until 52 weeks as well.

Both groups will receive standard exercise recommendations after 24 weeks and will be followed-up by clinical examination after 52 weeks. Echocardiographic variables (at rest and during exercise), quality of life, CPET, SPPB, strength testing, burden of AF, and cardiac biomarkers will be assessed. Changes between the end of the intervention period 24 weeks after diagnosis and the end of follow-up after 52 weeks will be analyzed. In addition, changes in variables between baseline and 52 weeks will be analyzed.

As an exploratory endpoint the incidence of cancer therapy-related cardiac dysfunction (CTRCD) and immune-checkpoint inhibitor- associated myocarditis (ICI-myocarditis) will be assessed after 24 and 52 weeks.

Detailed description: This is a prospective, randomized, controlled mono-center study investigating the effects of a combined, supervised aerobic exercise and resistance training in female patients with newly diagnosed TNBC (stage I-III) between 18 and 65 years of age scheduled for anthracycline-based chemotherapy and immunotherapy with checkpoint inhibitors. All patients will receive smart watches for rhythm monitoring. Patients will be advised to trigger electrocardiogram (ECG) measurements every day at 8 a.m., 2 p.m. and 8 p.m. as well as before and immediately after every training session (intervention group only). In addition, ECG should be recorded whenever symptoms occur.

Patients will be randomized (1:1) into a control group, receiving 24 weeks of standard exercise recommendations during neoadjuvant therapy, and an intervention group receiving 24 weeks of home-based, video-supervised exercise training consisting of endurance and resistance training.

At baseline clinical examination, quality of life, cardiac biomarkers, resting and stress echocardiography and CPET will be performed. SPPB and strength of the upper and lower body will be assessed.

Training in the intervention group will be performed 5x/week with 20 minutes/session and will contain resistance training and endurance training as a mixture between moderate continuous and high-intensity interval training. Training corridors based on heart rate will be prescribed with the aid of CPET testing at baseline and during follow-up visits. Intensity will be progressively increased, but will be individually adapted to the schedule and response to chemo- and immunotherapy.

Follow-up visits will be performed six and twelve weeks after diagnosis and clinical examination, cardiac biomarkers, resting and stress echocardiography and CPET as well as testing of muscle strength, SPPB, and quality of life will be repeated. Prescribed training corridors of heart rate will be adapted after each test. Upon clinical suspicion for adverse events, such as ICI-myocarditis, magnetic resonance imaging of the heart will be performed and training will not be continued.

The primary endpoint is the change of VO2peak between baseline and 24 weeks in the groups. Secondary endpoints include changes of variables between baseline and 24 weeks, including SPPB, cardiac biomarkers, quality of life, changes of strength of the upper and lower body (knee extensor and biceps muscles), variables of CPET, resting and stress echocardiography, and burden of AF. Changes in variables between baseline and after 52 weeks will also be analyzed. 24h- Holter monitoring will be performed at the end of weeks 24 and 52.

Both groups will receive standard exercise recommendations after 24 weeks and will be followed-up by clinical examination after 52 weeks: Resting and stress echocardiography, quality of life, CPET, SPPB, strength testing, AF burden, and cardiac biomarkers will be re-assessed.

As an exploratory endpoint the incidence CTRCD and ICI-myocarditis will be assessed after 24 and 52 weeks.

Eligibility criteria: Inclusion Criteria:

* Female patients with newly diagnosed, local triple-negative breast cancer (stage I-III) ≥ 18 to 65 years of age scheduled for immunochemotherapy with pembrolizumab and anthracycline-based chemotherapy

Exclusion Criteria:

* Unstable cardiac condition (clinical suspicion of progress or unstable coronary artery disease, signs of acute heart failure, haemodynamically relevant arrhythmias)
* Orthopaedic disability to exercise

Primary outcomes:
measure: Peak oxygen consumption (VO2peak) from baseline until the end of intervention
timeFrame: 24 weeks
Secondary outcomes:
measure: VO2peak from baseline to the end of follow-up
timeFrame: 52 weeks
measure: VO2peak from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Burden of atrial fibrillation (AF) from baseline to the end of intervention
timeFrame: 24 weeks
measure: Burden of AF from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Burden of AF from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Performance in short physical performance battery (SPPB) from baseline to end of intervention
timeFrame: 24 weeks
measure: Performance in SPPB from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Performance in SPPB from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Improvement of muscle strength of the upper (biceps curl) and lower extremity (knee extensor) from baseline to the end of intervention
timeFrame: 24 weeks
measure: Improvement of muscle strength of the upper (biceps curl) and lower extremity (knee extensor) from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Improvement of muscle strength of the upper (biceps curl) and lower extremity (knee extensor) from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Changes of resting and stress echocardiographic variables from baseline to the end of intervention
timeFrame: 24 weeks
measure: Changes of resting and stress echocardiographic variables from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Changes of resting and stress echocardiographic variables from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Cardiac biomarkers from baseline to the end of intervention
timeFrame: 24 weeks
measure: Cardiac biomarkers from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Cardiac biomarkers from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Change in quality of life from baseline to the end of intervention
timeFrame: 24 weeks
measure: Change in quality of life from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Change in quality of life from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Incidence of immune-checkpoint inhibitor associated myocarditis (ICI-myocarditis) from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Decrease of minute ventilation to carbon dioxide production (VE/VCO2) from baseline to the end of intervention
timeFrame: 24 weeks
measure: Decrease of VE/VCO2 from baseline to the end of follow-up
timeFrame: 52 weeks
measure: Decrease of VE/VCO2 from the end of intervention to the end of follow-up
timeFrame: 28 weeks
measure: Incidence of cancer treatment-related cardiac dysfunction (CTRCD) from baseline to the end of follow-up
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Munich
country: Germany
facility: Preventive Sports Medicine and Sports Cardiology
state: Bavaria
city: Munich
country: Germany
facility: Department of Medicine, Division of Prevention and Sports Medicine TU Munich
Study officials:
affiliation: Technical University of Munich
name: Simon Wernhart, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, Cutter DJ, de Azambuja E, de Boer RA, Dent SF, Farmakis D, Gevaert SA, Gorog DA, Herrmann J, Lenihan D, Moslehi J, Moura B, Salinger SS, Stephens R, Suter TM, Szmit S, Tamargo J, Thavendiranathan P, Tocchetti CG, van der Meer P, van der Pal HJH; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229-4361. doi: 10.1093/eurheartj/ehac244. No abstract available.
citation: Wernhart S, Rassaf T. Relevance of Cardiovascular Exercise in Cancer and Cancer Therapy-Related Cardiac Dysfunction. Curr Heart Fail Rep. 2024 Jun;21(3):238-251. doi: 10.1007/s11897-024-00662-0. Epub 2024 May 2.
citation: Wernhart S, Rassaf T. Exercise, cancer, and the cardiovascular system: clinical effects and mechanistic insights. Basic Res Cardiol. 2025 Feb;120(1):35-55. doi: 10.1007/s00395-024-01034-4. Epub 2024 Feb 14.
citation: Adams V, Reich B, Uhlemann M, Niebauer J. Molecular effects of exercise training in patients with cardiovascular disease: focus on skeletal muscle, endothelium, and myocardium. Am J Physiol Heart Circ Physiol. 2017 Jul 1;313(1):H72-H88. doi: 10.1152/ajpheart.00470.2016. Epub 2017 May 5.
citation: Ansund J, Mijwel S, Bolam KA, Altena R, Wengstrom Y, Rullman E, Rundqvist H. High intensity exercise during breast cancer chemotherapy - effects on long-term myocardial damage and physical capacity - data from the OptiTrain RCT. Cardiooncology. 2021 Feb 15;7(1):7. doi: 10.1186/s40959-021-00091-1.
citation: Antunes P, Joaquim A, Sampaio F, Nunes C, Ascensao A, Vilela E, Teixeira M, Capela A, Amarelo A, Marques C, Viamonte S, Alves A, Esteves D. Effects of exercise training on cardiac toxicity markers in women with breast cancer undergoing chemotherapy with anthracyclines: a randomized controlled trial. Eur J Prev Cardiol. 2023 Jul 12;30(9):844-855. doi: 10.1093/eurjpc/zwad063.
citation: Berling-Ernst A, Yahiaoui-Doktor M, Kiechle M, Engel C, Lammert J, Grill S, Dukatz R, Rhiem K, Baumann FT, Bischoff SC, Erickson N, Schmidt T, Niederberger U, Siniatchkin M, Halle M. Predictors of cardiopulmonary fitness in cancer-affected and -unaffected women with a pathogenic germline variant in the genes BRCA1/2 (LIBRE-1). Sci Rep. 2022 Feb 21;12(1):2907. doi: 10.1038/s41598-022-06913-1.
citation: Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, Civelli M, Lamantia G, Colombo N, Curigliano G, Fiorentini C, Cipolla CM. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015 Jun 2;131(22):1981-8. doi: 10.1161/CIRCULATIONAHA.114.013777. Epub 2015 May 6.
citation: Fardman A, Banschick GD, Rabia R, Percik R, Fourey D, Segev S, Klempfner R, Grossman E, Maor E. Cardiorespiratory fitness and survival following cancer diagnosis. Eur J Prev Cardiol. 2021 Sep 20;28(11):1242-1249. doi: 10.1177/2047487320930873. Epub 2020 Jul 19.
citation: Foulkes SJ, Howden EJ, Haykowsky MJ, Antill Y, Salim A, Nightingale SS, Loi S, Claus P, Janssens K, Mitchell AM, Wright L, Costello BT, Lindqvist A, Burnham L, Wallace I, Daly RM, Fraser SF, La Gerche A. Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study. Circulation. 2023 Feb 14;147(7):532-545. doi: 10.1161/CIRCULATIONAHA.122.062814. Epub 2022 Nov 7.
citation: Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J; KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022 Feb 10;386(6):556-567. doi: 10.1056/NEJMoa2112651.
citation: van der Schoot GGF, Ormel HL, Westerink NL, May AM, Elias SG, Hummel YM, Lefrandt JD, van der Meer P, van Melle JP, Poppema BJ, Stel JMA, van der Velden AWG, Vrieling AH, Wempe JB, Ten Wolde MG, Nijland M, de Vries EGE, Gietema JA, Walenkamp AME. Optimal Timing of a Physical Exercise Intervention to Improve Cardiorespiratory Fitness: During or After Chemotherapy. JACC CardioOncol. 2022 Oct 18;4(4):491-503. doi: 10.1016/j.jaccao.2022.07.006. eCollection 2022 Nov.