Adverse Myocardial and Vascular Side Effects of Immune Checkpoint Inhibitors (AMICI)

Atteintes Myocardiques, péricardiques et Vasculaires Sous Simple et/ou Double immunothérapie Anti-cancéreuse Anti-PD1, antiPDL1 et Anti-CTLA4

Our knowledge on cardiovascular side effects of immune checkpoint inhibitors (ICIs) is restricted to this date to observational retrospective data (mainly case series and pharamcovigilance analysis). We aim at assessing the incidence of cardiovascular adverse side effects of ICIs by means of a prospective interventional single centre study using multiple biomarkers.

Study Overview

• Status: Completed
• Conditions: Cancer; Cardiovascular Abnormalities; Immune Defect
• Intervention / Treatment: Diagnostic test: Cardiac MRI; Device: Smart cloth; Other: Biobanking

Detailed Description

Immune checkpoint inhibitors (ICIs) are drastically improving cancer prognosis. Cardiovascular adverse side effects of ICIs are though to be rare but may be responsible for ~50% death rates.

Prospective screening for cardiovascular and muscular immune related side effects has not been undertaken independently from the industry.

The aim is to describe the incidence of these side effects by means of serial assessment in patients undergoing ICI therapy for cancer. Biomarkers as ECG, echocardiography, cardiac magnetic resonance imaging and long-term ECG monitoring will be undertaken at inclusion (before ICI therapy is started), and during the first cycle treatments and at 6 months follow-up.

Mean endpoint encompasses cardiovascular and muscular adverse side effects between the 2nd and the 3rd ICI cycle. Secondary endpoints include cardiovascular and muscular adverse side effects at 6 months follow-up, and the incidence of individual side effects.

4 ancillary studies based on patients' blood biobanking are also planned. Their objectives are:

• to assess sensitivity of heart failure biomarkers in predicting cardiovascular events under ICI,
• to assess sensitivity of cytokine biomarkers in predicting cardiovascular events under ICI,
• to bank cells to induce cardiomyocytes from stem cells
• to bank DNA to identify genetic factors related to occurrence of cardiovascular events under ICI

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • AP-HP - Hopital Europeen Georges-Pompidou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing ICI therapy for cancer before the start of treatment.

Description

Inclusion Criteria:

- prescribed treatment by immune checkpoint inhibitors (ICI) for cancer

Exclusion Criteria:

• previous treatment by any ICI
• any contraindication to cardiac resonance magnetic imaging
• contraindication to gadoteric acid, meglumin or any gadolinium-based contrast agent
• pace maker or automated implantable defibrilator
• pregnancy, breastfeeding
• women of childbearing potential who do not use one of the following methods of birth control: hormonal contraception or intrauterine device or bilateral tubal occlusion
• patient under legal protection
• renal failure defined by creatinine clearance <30ml/min/m² (CKD-EPI)
• current participation or exclusion period of another interventional clinical study

Exclusion Criteria for ancillary studies:

- hemoglobinemia < 9 g/dl

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients

Diagnostic test: Cardiac MRI; Gadolinium-enhanced magnetic resonance imaging of the heart before the first cycle of chemotherapy; Device: Smart cloth; A smart cloth recording cardiac and hemodynamic parameters will be worn by patients during 42 days. Replaced by a holter monitor if the smart cloth is refused or not tolerated by the patient.; Other: Biobanking; Blood samples (plasma, serum, DNA, stem cells, immune cells) taken as part of the study will be stored in a biological sample collection. These samples may be used for further analysis not described in the initial protocol but which may be useful for investigation or in light of advances in scientific knowledge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with major cardiovascular advserse drug reactions	Incidence of a composite endpoint including myocarditis, pericarditis, acute coronary syndrome, acute heart failure, subclinial cardio-toxicity, high degree conduction abormalities or ventricular sustained arrythmias, cardiovascular death.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with major cardiovascular advserse drug reactions	Incidence of a composite endpoint including myocarditis, pericarditis, acute coronary syndrome, acute heart failure, subclinial cardio-toxicity, high degree conduction abormalities or ventricular sustained arrythmias, cardiovascular death.	6 months
Number of patients with other cardiovascular advserse drug reactions	Incidence of a composite endpoint including vasculitis or myositis.	6 weeks and 6 months
Number of patients with isolated CMR abnormalities	Serial assessment	6 weeks and 6 months
Number of patients with rhythm abnormalities that do not fullfill major advsere event criteria	Burden of extrasystole, low degree conduction disorders	6 weeks and 6 months
Risk factors for cardiovascular adverse drug event	Characterization of risk predictors for occurrence of cardiovascular adverse drug event, among the following: socio-demographic characteristics, oncologic characteristics, previous treatments, serum biomarkers, patient assessment on ESC-SCORE and ACC/AHA ASCVD risk scoring systems, immune status, cardiac characteristics on imaging.	6 weeks and 6 months

Other Outcome Measures

Outcome Measure	Time Frame
Biomarkers level of heart failure	Baseline
Cytokinic biomarkers level	Baseline

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fédération Française de Cardiologie; BioSerenity
• Investigators: Principal Investigator: Mariana Mirabel, MD, Inserm U970 Paris Cardiovascular Research Center

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2020
• Primary Completion (Actual): February 1, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: October 7, 2020
• First Submitted That Met QC Criteria: October 7, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): June 8, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cancer; Myositis; Cardiotoxicity; Pericarditis; Immune checkpoint inhibitors; Myocarditis; Thrombotic events
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities
• Other Study ID Numbers: APHP191048; 2020-A01502-37 (Other Identifier: Agence nationale de sécurité du médicament et des produits de santé)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared
• IPD Sharing Time Frame: Two years after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractual agreement. Processing of shared data must comply with European General Data Protection Regulation (GDPR).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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