CARDiac Toxicity Following ImmunOtherapy Treatment for Melanoma (CARD-IO)

CARD-IO - CARDiac Toxicity Following ImmunOtherapy Treatment for Melanoma

People who develop a type of skin cancer known as 'melanoma' are often treated with immunotherapy. The type of immunotherapy used for patients with melanoma is known as Immune Checkpoint Inhibitors (ICI). While ICI is very successful, it can lead to negative side effects that are known as 'immune related adverse events' (irAEs). These irAEs can affect any part of the body and can range in severity from mild symptoms to death.

There has been a lot of research on irAEs that occur during ICI, but less is known about how irAEs can affect people in the long-term.

Although irAEs are common from ICI, acute irAEs affecting the heart (cardiac irAEs) are uncommon. However, as they relate to the heart, they are often serious and have a higher rate of death compared to other types of irAEs. Little is known regarding the long-term effects of ICI on the heart. However, there is some evidence to suggest that ICI may also cause long-term cardiac irAEs such as accelerating a build-up of fatty materials in the arteries known as 'atherosclerosis' and inflammation of plaque in the heart. This can lead to an increased risk of heart attack.

Although there are guidelines for patients on ICI treatment to receive investigations to look for irAEs, including cardiac irAEs, there are no guidelines for monitoring long-term survivors.

The aim of the CARD-IO study is to establish if it is possible to investigate in long-term follow-up cardiac side-effects in patients who received ICI for melanoma. The data for this study would be used to support a larger study in the same patient population. Potentially, this could lead to a change in guidelines and long-term follow-up care for melanoma patients who have received ICI.

Study Overview

• Status: Enrolling by invitation
• Conditions: Melanoma Stage III or IV
• Intervention / Treatment: Diagnostic test: Transthoracic Echocardiogram; Diagnostic test: Cardiac MRI; Diagnostic test: Cardiac Biomarker Screening; Other: Basic Observations; Diagnostic test: 12-Lead ECG

Detailed Description

Primary aim • To establish the feasibility of conducting a study to investigate late cardiac side effects caused by immunotherapy in patients with melanoma in order to generate data to support a larger study in this patient population.

Secondary aims

• To assess factors impacting on the acceptance and adherence with cardiac investigations.
• To contribute to the understanding of long-term cardiac toxicities following immunotherapy which will enable their early recognition.

Primary endpoint

• Acceptance rate (reported as the total number of patients consented divided by the number of patients invited for the study).

Secondary endpoints

• Adherence rate (reported as the proportion of patients completing all the scheduled cardiac screening tests divided by the number of patients enrolled in the study).
• Recruitment rate (reported as the number of patients recruited on average per month in each site, and overall).
• Reasons for non-adherence or declining to consent.
• Difference in adherence rates between adjuvant early disease setting and metastatic setting.
• Proportion of patients who experience cardiac irAEs during long-term follow-up, post-treatment.
• Prevalence of cardiac irAEs.

The planned sample size is 60 participants.

The project will assess 3 groups of patients at different timepoints during their standard of care surveillance, at 2-4, 5-7 and 8-10 years following the completion of their immunotherapy treatment for melanoma. Patients on routine follow-up, at 2 to 10 years following the completion of immunotherapy treatment for melanoma will be identified by searching through database of patients with melanoma who received immune checkpoint inhibitors (ICI). Patients respecting the inclusion criteria will be invited to take to part to the study.

Patients included in the study will undergo screening blood tests including cardiac biomarkers (troponin I, NTproBNP, lipid profile, HbA1c, ferritin), a 12 lead ECG and transthoracic echocardiography, a cardiac MRI alongside completing a questionnaire about cardiac events and risk factors. Patients will have blood tests done at Royal Marsden or Royal Free, while all the other cardiac investigations (ECG, transthoracic echocardiography, cardiac MRI) will be performed at the Royal Brompton Hospital. Surveillance imaging performed as per standard of care at the Royal Marsden or at the Royal Free will be reviewed for evidence of atherosclerosis by the team at the Royal Brompton. The cardiology team at the Royal Brompton will review cardiac investigations' results and abnormal results will be flagged.

A summary report will be generated and sent to the patients, their GPs, and the Site irrespective of the results found, and abnormal results will be investigated as per standard of care. The prevalence of cardiac adverse events will be summarised.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW6 3JJ
    • The Royal Marsden NHS Foundation Trust

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients from The Royal Marsden NHS Foundation Trust (RMH) and the Royal Free London NHS Trust (RFH) who are in follow up after receiving immunotherapy for melanoma 2-10+ years prior to enrolment.

Description

Inclusion Criteria:

• Written informed consent
• Age 18 years or older
• Confirmed diagnosis of melanoma
• Stage IIB or IIC or stage III or stage IV melanoma
• Previous immunotherapy with immune-checkpoint inhibitors (anti PD-(L)1 +/- anti CTLA-4) for melanoma
• On standard of care surveillance, at 2 to 10+ years following the completion of immunotherapy treatment

Exclusion Criteria:

• Medical or psychological condition that would preclude informed consent.
• Known contraindications to MRI, such as claustrophobia, pregnancy, or indwelling metallic implant which is not MR conditional
• Current active treatment with systemic therapy for any malignancy.
• Active treatment with systemic therapy for any malignancy started after the completion of immunotherapy for melanoma.
• Subjects unable to comply with the study or sample schedule.
• Planned participation in a drug trial receiving investigational agents.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
2-4 years; Patients on routine follow-up 2-4 years after the completion of immunotherapy treatment for melanoma	Diagnostic test: Transthoracic Echocardiogram; A transthoracic echocardiogram will be performed in accordance to standard British Society of Echocardiography guidelines. This will involve undertaking an ultrasound scan of the participant's heart with ultrasound jelly to obtain information including left ventricular function and valvular function. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac MRI; A cardiac MRI scan will be performed in order to assess the morphology and function of the heart in accordance with international guidelines. Data that will be derived includes biventricular volumes and function and myocardial strain data. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac Biomarker Screening; Cardiac Troponin I,; NTproBNP],; lipid profile,; HbA1c; ferritin These are Standard of Care tests being performed at a non Standard of Care timepoint; Other: Basic Observations; Heart rate; Blood pressure; Oxygen SAT; Respiratory rate These are Standard of Care observations being performed at a non Standard of Care timepoint; Diagnostic test: 12-Lead ECG; Participants will undergo a standard 12-lead ECG in order to record the electrical activity of the heart. This typically takes a few minutes and the ECG is read by a cardiologist This is a Standard of Care test being performed at a non Standard of Care timepoint
5-7; Patients on routine follow-up 5-7 years after the completion of immunotherapy treatment for melanoma	Diagnostic test: Transthoracic Echocardiogram; A transthoracic echocardiogram will be performed in accordance to standard British Society of Echocardiography guidelines. This will involve undertaking an ultrasound scan of the participant's heart with ultrasound jelly to obtain information including left ventricular function and valvular function. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac MRI; A cardiac MRI scan will be performed in order to assess the morphology and function of the heart in accordance with international guidelines. Data that will be derived includes biventricular volumes and function and myocardial strain data. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac Biomarker Screening; Cardiac Troponin I,; NTproBNP],; lipid profile,; HbA1c; ferritin These are Standard of Care tests being performed at a non Standard of Care timepoint; Other: Basic Observations; Heart rate; Blood pressure; Oxygen SAT; Respiratory rate These are Standard of Care observations being performed at a non Standard of Care timepoint; Diagnostic test: 12-Lead ECG; Participants will undergo a standard 12-lead ECG in order to record the electrical activity of the heart. This typically takes a few minutes and the ECG is read by a cardiologist This is a Standard of Care test being performed at a non Standard of Care timepoint
8-10+; Patients on routine follow-up 8-10+ years after the completion of immunotherapy treatment for melanoma	Diagnostic test: Transthoracic Echocardiogram; A transthoracic echocardiogram will be performed in accordance to standard British Society of Echocardiography guidelines. This will involve undertaking an ultrasound scan of the participant's heart with ultrasound jelly to obtain information including left ventricular function and valvular function. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac MRI; A cardiac MRI scan will be performed in order to assess the morphology and function of the heart in accordance with international guidelines. Data that will be derived includes biventricular volumes and function and myocardial strain data. This is a Standard of Care test being performed at a non Standard of Care timepoint; Diagnostic test: Cardiac Biomarker Screening; Cardiac Troponin I,; NTproBNP],; lipid profile,; HbA1c; ferritin These are Standard of Care tests being performed at a non Standard of Care timepoint; Other: Basic Observations; Heart rate; Blood pressure; Oxygen SAT; Respiratory rate These are Standard of Care observations being performed at a non Standard of Care timepoint; Diagnostic test: 12-Lead ECG; Participants will undergo a standard 12-lead ECG in order to record the electrical activity of the heart. This typically takes a few minutes and the ECG is read by a cardiologist This is a Standard of Care test being performed at a non Standard of Care timepoint

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptance rate	total number of patients consented divided by the number of patients invited for the study	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence rate	proportion of patients completing all the scheduled cardiac screening tests divided by the number of patients enrolled in the study	12 months
Recruitment rate	Number of patients recruited on average per month in each site, and overall	12 months
Reasons for non-adherence or declining to consent	Reasons for non-adherence or declining to consent	12 months
Proportion of patients who experience cardiovascular irAEs	Proportion of patients who experience cardiovascular irAEs during long-term follow-up, post-treatment	12 months
Prevalence of cardiac irAEs	Prevalence of cardiac irAEs	12 months
Difference in adherence rates	Difference in adherence rates between adjuvant early disease setting and metastatic setting	12 months

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Royal Free Hospital NHS Foundation Trust; Royal Brompton & Harefield NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2025
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: September 18, 2024
• First Submitted That Met QC Criteria: September 18, 2024
• First Posted (Actual): September 20, 2024

Study Record Updates

• Last Update Posted (Estimated): October 1, 2025
• Last Update Submitted That Met QC Criteria: September 26, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: melanoma; cardiac toxicity; immune related adverse events; immunotherapy treatment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Wounds and Injuries; Pathologic Processes; Neoplasms by Site; Neoplasms; Heart Diseases; Neoplasms by Histologic Type; Chemically-Induced Disorders; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Nevi and Melanomas; Skin Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Melanoma; Cardiotoxicity; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Electrodiagnosis; Cardiac Imaging Techniques; Ultrasonography; Electrocardiography; Echocardiography
• Other Study ID Numbers: CCR6063

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is a feasibility study to support the application of a larger more complex study by the same team on the same topic. Sharing of IPD would require additional consents and level of complexity in the Data Plan which current resource restraints does not allow. This will be considered for future studies based on this research.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No