CAVACI: Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors
Study Details
Study Description
Brief Summary
The goal of this prospective, multicentre study is to investigate short- and long-term cardiovascular effects in cancer patients treated with immune checkpoint inhibitors (ICIs).
The main question[s] it aims to answer are:
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To evaluate cardiac markers and their possible relationship with cardiac abnormalities
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To estimate the incidence of cardiac adverse events of ICIs in a real world population
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To predict and detect cardiac abnormalities in an earlier (subclinical) stage
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To investigate possible progression of coronary atherosclerosis
Participants will be closely monitored by performing the following additional visits and testing:
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Chest CT scan prior to treatment start, after 12 and 24 months.
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Consultation with a cardiologist at baseline, 3, 6, 12 and 24 months, who will perform an electrocardiogram and echocardiogram.
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One additional blood sample prior to treatment start, after 3, 6, 12 and 24 months. An extra blood sample could be taken in case of sudden heart problems.
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Non-invasive endothelial function tests prior to treatment start, after 12 and 24 months.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular immune related adverse events (irAEs). The current guidelines are based on anecdotal evidence and expert opinions due to the lack of solid data and prospective studies. Therefore, cardiac monitoring, in patients receiving ICIs, is often not implemented by oncologists as many questions remain unanswered. Hence, the urgent need to investigate the possible short and long term cardiovascular effects of ICIs.
The investigators developed a multicentre, prospective study in which patients with a solid tumour eligible for ICI treatment will be enrolled. The study exists of routine investigations of blood parameters (troponin and (N-terminal) brain-type natriuretic peptide levels in particular) and a thorough cardiovascular follow-up on fixed time points during a period of two years. The cardiovascular follow-up consists of continuous remote patient monitoring, routine cardiology consultations including electrocardiograms, transthoracic echocardiograms, CT-scans for calcium scoring and non-invasive endothelial function tests. Associations between these blood parameters and short and long term cardiovascular irAEs will be statistically analysed.
This project will allow for a better estimate of the incidence of both short and long-term cardiovascular irAEs in a 'real world' patient population receiving ICIs. If the investigators are able to accurately predict and detect short- and long-term cardiovascular irAEs in an early (and subclinical) stage by correct implementation and interpretation of existing cardiac markers, they could be managed early on in a more effective manner.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Cancer patients with a solid tumour eligible for treatment with immune checkpoint inhibitors Patients are treated as standard of care |
Procedure: Cardiology consultation
Electrocardiogram (ECG).
Echocardiogram: A comprehensive evaluation of systolic and diastolic function, ventricular and atrial geometry will be performed. Special attention will be given to acquire a 3D measurement of left ventricular ejection fraction (LVEF) and to perform deformation imaging of left ventricle (global longitudinal strain (GLS)). Right ventricular geometry and function will be evaluated by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE). Diastolic dysfunction will be based on average E/e' ratio > 15 and left atrial (LA) area > 30 cm2.
Diagnostic Test: Chest Computed Tomography (CT) without contrast
Calcium score. This will be performed at baseline, 12 and 24 months. The scans at 12 and 24 months will be combined with standard of care scans for cancer treatment.
Other Names:
Procedure: Non-invasive endothelial function tests
FMD
PAT
This aspect of the study will only be performed in the patients included by the Antwerp University Hospital due to organizational/practical issues.
Other Names:
Procedure: Electrocardiogram
An ECG will be taken prior to each ICI cycle during the first three months of treatment.
Other Names:
Diagnostic Test: Extra serum sample (7.5 mL)
An extra serum sample will be taken at baseline, 3, 6, 12, 24 months and in case of sudden cardiac problems. This will subsequently be analysed to determine high-sensitivity troponin I, high-sensitivity troponin T and NT-proBNP.
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Outcome Measures
Primary Outcome Measures
- The incidence of a three-fold increase of high-sensitivity troponin I (hs-TnI)/T (hs-TnT) within the first three months of treatment compared to baseline levels. [3 months after last patient is included (31 January 2024)]
Proportions and 95% confidence interval
Secondary Outcome Measures
- The prevalence of hs-TnT/hs-TnI above the Upper Limit of Normal (ULN) at the different visits i.e. baseline, 3, 6, 12 and 24 months. [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- The prevalence of NT-proBNP above the ULN at the different visits i.e. baseline, 3, 6, 12 and 24 months. [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Evolution of hs-TnT/hs-TnI levels at 3, 6, 12 and 24 months compared to baseline. [Through study completion, an average of 1 year]
Studied in linear mixed effects model with a random intercept per subject to account for the correlation of measurements coming from the same individual. This model will be extended with patient and treatment characteristics, to evaluate impact of these on the evolution of troponin and pro-BNP levels (including proportions and 95% confidence intervals)
- Evolution of N terminal brain-type natriuretic peptide (NT-proBNP) levels at 3, 6, 12 and 24 months compared to baseline. [Through study completion, an average of 1 year]
Studied in linear mixed effects model with a random intercept per subject to account for the correlation of measurements coming from the same individual. This model will be extended with patient and treatment characteristics, to evaluate impact of these on the evolution of troponin and pro-BNP levels (including proportions and 95% confidence intervals)
- Association between troponin elevations (both crude and categorized values) and cardiovascular abnormalities at 3 months, 6 months, 12 months, and 24 months. [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Association between NT-proBNP elevations (both crude and categorized values) and cardiovascular abnormalities at 3 months, 6 months, 12 months, and 24 months. [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Association between troponin levels, NT-proBNP and 2-year overall survival. [Through study completion, an average of 1 year]
Cox proportional hazard model with time dependent covariates.Kaplan-Meier curves will be used for visualization. 2-year survival rates and 95% confidence intervals will be reported for each subgroup based on the maximal measured increase from baseline (≤ 1.5 x baseline values; > 1.5 x baseline values and < 3 x baseline values; ≥ 3 x baseline values)(including proportions and 95% confidence intervals)
- To determine the appropriate cut-off level of troponin baseline levels as a predictor for cardiovascular abnormalities or MACE. [Through study completion, an average of 1 year]
Receiver Operating Characteristic (ROC) curve based on logistic model including proportions and 95% confidence intervals)
- Assess agreement between hs-TnT and hs-TnI levels at baseline, 3 months, 6 months, 12 months, and 24 months. [Through study completion, an average of 1 year]
Bland-Altman curves and intraclass correlation coefficient based on a two-way mixed effects model (including 95% confidence intervals)
- Association between the grade of troponin elevations (highest value; both crude and categorized values) at 3 months, 6 months, 12 months and 24 months, and major adverse cardiac events (MACE). [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Association between troponin elevations (both crude and categorized values) and severe immune related non-cardiovascular toxicities. [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Association between the grade of NT-proBNP elevations (highest value; both crude and categorized values) at 3 months, 6 months, 12 months and 24 months, and major adverse cardiac events (MACE). [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Association between NT-proBNP elevations (both crude and categorized values) and severe immune related non-cardiovascular toxicities. [Through study completion, an average of 1 year]
Logistic mixed effect model including a random intercept per subject (including proportions and 95% confidence intervals)
- Prevalence of severe immune-related non-cardiovascular toxicities (grade 3-5) [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Diastolic function (graded based on doi: 10.1016/j.echo.2016.01.011.) at baseline, 3 months, 6 months, 12 months, and 24 months [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Prevalence of major adverse cardiac events (MACE) at 3 months, 6 months, 12 months, and 24 months. [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Prevalence of cardiovascular abnormalities at 3 months, 6 months, 12 months, and 24 months based on a predefined classification system with inclusion of pericardial effusion and new arrhythmias (doi:10.1093/eurheartj/ehaa006). [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Calcium score at baseline, 12 months, and 24 months. [Through study completion, an average of 1 year]
Proportions and 95% confidence interval
- Peripheral vascular function at baseline, 3 months, 6 months, 12 months and 24 months. [Through study completion, an average of 1 year]
Flow mediated dilatation: dilatation % from baseline to maximal post-occlusion diameter. Peripheral arterial tonometry ratio: based on the response to reactive hyperemia using post and pre-occlusion values
- Grade troponin elevations into three different categories according to their change to baseline values at three months. [3 months after last patient is included (31 January 2024)]
Group 1: ≤ 1.5 x baseline values Group 2: > 1.5 x baseline values and < 3 x baseline values Group 3: ≥ 3 x baseline values
- Grade NT-proBNP elevations into three different categories according to their change to baseline values at three months. [3 months after last patient is included (31 January 2024)]
Group 1: ≤ 1.5 x baseline values Group 2: > 1.5 x baseline values and < 3 x baseline values Group 3: ≥ 3 x baseline values
- Association between patient characteristics and troponin/NT-proBNP levels in the first 3 months, at 6 months, 12 months, and 24 months of ICI therapy. [Through study completion, an average of 1 year]
Studied in linear mixed effects model with a random intercept per subject to account for the correlation of measurements coming from the same individual. This model will be extended with patient and treatment characteristics, to evaluate impact of these on the evolution of troponin and pro-BNP levels (including proportions and 95% confidence intervals)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Have a solid tumour and will receive one of the following therapies based on current evidence based clinical guidelines: anti-programmed cell death protein-1 (PD-1), anti-programmed cell death ligand-1 (PD-L1) and/or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy
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Be literate in Dutch or English
Exclusion Criteria:
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Prior treatment with immunotherapy (immune checkpoint inhibitors, T-cell transfer therapy, cancer treatment vaccines or immune system modulators).
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Patients who will receive ICIs in combination with an additional regimen (chemotherapy, tyrosine kinase inhibitors,…).
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Having a known history of human immunodeficiency virus (HIV) infection.
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Having a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as detectable RNA via qualitative nucleic acid testing) infection.
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Having a diagnosis of immunodeficiency or is receiving chronic/active systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | AZ Sint-Vincentius Deinze | Deinze | East-Flanders | Belgium | 9800 |
| 2 | Algemeen Ziekenhuis Maria Middelares | Ghent | East-Flanders | Belgium | 9000 |
| 3 | AZ Sint-Elisabeth Zottegem | Zottegem | East-Flanders | Belgium | 9620 |
| 4 | Antwerp University Hospital | Antwerp | Belgium | 2650 |
Sponsors and Collaborators
- Algemeen Ziekenhuis Maria Middelares
Investigators
- Principal Investigator: Christof Vulsteke, Prof, Algemeen Ziekenhuis Maria Middelares
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MMS.2021.058