Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors

Cancer Clinical Trial

— CAVACI  

Official title:

Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors: a Prospective Multicentre Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05699915
• Other study ID #: MMS.2021.058
• Status: Recruiting
• Phase: N/A
• Start date: January 7, 2022
• Est. completion date: November 30, 2026

Study information

• Verified date: May 2023
• Source: Algemeen Ziekenhuis Maria Middelares
• Contact: Christof Vulsteke, Prof
• Phone: +3292469522
• Email: Christof.Vulsteke[@]azmmsj.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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:

• To investigate troponin and NT-proBNP values in patients receiving ICIs and their association with ICI-induced CV abnormalities and MACEs.

• Study the calcium score, systolic, and diastolic (dys)function.

• Evaluate associations between patient/disease characteristics / transthoracic echocardiography parameters / electrocardiography parameters and troponin / NT-proBNP levels.

Participants will be closely monitored by performing the following additional visits and testing:

• Chest CT scan prior to treatment start, after 12 and 24 months.

• Consultation with a cardiologist at baseline, 3, 6, 12 and 24 months, who will perform an electrocardiogram and echocardiogram.

• 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.

• Non-invasive endothelial function tests prior to treatment start, after 12 and 24 months.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 276
• Est. completion date: November 30, 2026
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

• Be literate in Dutch or English

Exclusion Criteria:

• Prior treatment with immunotherapy (immune checkpoint inhibitors, T-cell transfer therapy, cancer treatment vaccines or immune system modulators).

• Patients who will receive ICIs in combination with an additional systemic anti-cancer regimen (chemotherapy, tyrosine kinase inhibitors,…).

• Having a known history of human immunodeficiency virus (HIV) infection.

• 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.

• Having a diagnosis of immunodeficiency or is receiving chronic/active systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent)

Related Conditions & MeSH terms

• Atherosclerosis
• Cancer
• Cardiotoxicity
• Diastolic Dysfunction
• Immune-related Adverse Event
• Myocarditis

Intervention

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)). The right ventricular function will be evaluated by tricuspid annular plane systolic excursion (TAPSE) and peak systolic velocity S' derived from color coded tissue Doppler imaging (TDI). 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, if possible, with standard of care scans for cancer treatment.

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.
• Electrocardiogram
An ECG will be taken prior to each ICI cycle during the first three months of treatment.

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.

Locations

Country	Name	City	State
Belgium	Antwerp University Hospital	Antwerp
Belgium	AZ Sint-Vincentius Deinze	Deinze	East-Flanders
Belgium	Algemeen Ziekenhuis Maria Middelares	Ghent	East-Flanders
Belgium	AZ Sint-Elisabeth Zottegem	Zottegem	East-Flanders

Sponsors (1)

Lead Sponsor	Collaborator
Algemeen Ziekenhuis Maria Middelares

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of an elevated hs-TnT above the ULN if the baseline value was normal; or 1.5 = times baseline if the baseline value was above the ULN within the first three months of treatment. The maximum measured value will be taken into account.	For the primary endpoint, the cumulative incidence of troponin elevation will be calculated with death as a competing risk. Cumulative incidences and corresponding 95% confidence intervals will be reported and a cumulative incidence plot will be used to visualize the results.	Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and 3 months after last patient is included.
Secondary	The incidence of hs-TnT/NT-proBNP elevations at 6, 12, and 24 months.	Cumulative incidences and 95% confidence intervals, considering death as a competing event.	Through study completion, an average of 1 year
Secondary	The incidence of hs-TnT/NT-proBNP elevations at baseline, 3, 6, 12, and 24 months.	Cumulative incidences and 95% confidence intervals, considering death as a competing event.	Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Evolution of hs-TnT/NT-proBNP in 24 months compared to baseline.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.	Through study completion, an average of 1 year
Secondary	Evolution of transthoracic 3D echocardiography parameters (dimensions, diastolic function, valvular abnormalities, LVEF, strain analysis) at baseline, 3, 6, 12, and 24 months.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Evolution of electrocardiography parameters (rhythm, heart axis, PQ interval, QRS duration, bundle branch block, QT interval, RR interval, pathological Q's, left ventricular hypertrophy and STT segments) at baseline, 3, 6, 12, and 24 months.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and transthoracic echocardiography parameters at baseline, 3, 6, 12, and 24 months.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and electrocardiography (rhythm, heart axis, PQ, QRS, bundle branch block, QT, RR, pathological Q's, left ventricular hypertrophy and STT segments) parameters at baseline, 3, 6, 12, and 24 months.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Cumulative incidence of cardiovascular (CV) abnormalities at 3, 6, 12, and 24 months based on the CARDIOTOX classification system of Sendón et al., with the inclusion of pericardial effusion and new arrhythmias.	Cumulative incidences and 95% confidence intervals, considering death as a competing event.	Through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and CV abnormalities (as classified based on the CARDIOTOX classification for myocardial injury including cardiac biomarkers, symptoms, LVEF, LA area, LVESV, GLS and diastolic function).	Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.	Through study completion, an average of 1 year
Secondary	Cumulative incidence of MACEs at 3, 6, 12, and 24 months. MACEs were defined as the composite outcome of nonfatal stroke, nonfatal myocardial infarction, hospital admission for heart failure (HF) and cardiac revascularization, and CV death.	Cumulative incidences and 95% confidence intervals, considering death as a competing event.	Through study completion, an average of 1 year
Secondary	Overall survival.	Cumulative incidences and 95% confidence intervals	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and MACEs over a period of two years. Nonfatal stroke, nonfatal myocardial infarction, hospital admission for heart failure, cardiac revascularization and CV death will be combined to report MACEs.	Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.	Through study completion, an average of 1 year
Secondary	The difference in the evolution of hs-TnT/NT-proBNP between combination therapy and monotherapy over a period of two years.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	The difference in the evolution of transthoracic echocardiography parameters (dimensions, diastolic function, valvular abnormalities, LVEF, strain analysis) between combination therapy and monotherapy over a period of two years.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	The difference in the evolution of electrocardiography parameters (rhythm, heart axis, PQ, QRS, bundle branch block, QT, RR, pathological Q's, left ventricular hypertrophy and STT segments) between combination therapy and monotherapy.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and troponin.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and NT-proBNP.	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	Agreement between hs-TnT and hs-TnI levels at baseline, 3, 6, 12, and 24 months.	Bland-Altman curves and intraclass correlation coefficient (ICC) based on a two-way mixed effects model. The ICC and 95% confidence interval will be reported.	reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Secondary	The proportion of severe immune-related non-CV toxicities (grades 3-5).	Proportions and 95% confidence interval	Through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and severe immune-related non-CV toxicities (grades 3-5, e.g. pneumonitis, colitis, thyroiditis, etc. according to the CTCAE criteria).	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	Association between the evolution of troponin/NT-proBNP and overall survival.	Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.	Through study completion, an average of 1 year
Secondary	Association between the evolution of troponin and diastolic function (based on the recommendations listed in https://doi.org/10.1016/j.echo.2016.01.011, mitral inflow, tissue doppler imaging parameters).	Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.	Through study completion, an average of 1 year
Secondary	Calcium score at baseline, 12 months, and 24 months.	Proportions and 95% confidence interval	Through study completion, an average of 1 year
Secondary	Peripheral vascular function at baseline, 3 months, 6 months, 12 months and 24 months.	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	Through study completion, an average of 1 year
Secondary	Association between the evolution of troponin and calcium score.	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	Through study completion, an average of 1 year