Genetic Determinants of Myocarditis Induced by Immune-checkpoint Inhibitors

NCT06734689 | Recruiting

• 2 other identifiers: APHP2209212024-A00410-47
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

Immune checkpoint inhibitors (ICI) are active in multiple cancers. Their main drawback is the incidence of immune related adverse events; among which ICI-myocarditis (ICIM) is rare but can be the most life-threatening (up to 50% lethal). ICIM is due to ICI unleashing cytotoxic auto-reactive T-cells recognizing a culprit target antigen located on muscles and destroying them. Most often, ICIM occurs within a systemic ICI-myotoxicity, with peripheral muscular involvement (ICI-myositis), mimicking eventually myasthenia-gravis syndrome. Human Leukocyte Antigen (HLA) are cell surface proteins key for the regulation of the immune system acting via presentation of culprit antigens by antigen presenting cells (macrophages) to T-cells, subsequently triggering the destruction/tolerance of cells carrying this antigen. The HLA system (chromosome 6) is the most polymorphic region in the human genome and is associated with auto-immunity including myocarditis. HLA class I alleles have been strongly associated with some T-cell-mediated drug hypersensitivity reactions with handful patients needed to be tested to prevent a single case, leading to globally required cost-effective HLA typing pre-prescription for some drugs.

Conditions

ICI-myocarditis

Keywords

Myocarditis; Myositis; Immune-checkpoint inhibitors; Pharmacogenetic

Outcome Measures

Primary Outcomes (2)

• Identify common and rare variants in HLA regions and elsewhere in the genome associated with ICI Myocarditis.

  -Identify common single nucleotide variants(SNV) associated with ICI-myocarditis, such as variants in HLA regions with a genome-wide association study using 100 ICIM and 400 ICI-controls. Any association that reach the genome wide significance levels of 5.10-8 as well as any association mapping to candidate HLA and immune checkpoint genes with p-value\<10-5 will be tested for replication in an external international validation cohort.

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

• Identify common and rare variants in HLA regions and elsewhere in the genome associated with ICI

  -Sequence the entire protein-coding regions of the genome of all patients to identify extremely rare SNV associated with a strong risk of ICI-myocarditis. Investigators will focus on the search of rare SNV that are present only in the group of ICI-myocarditis patients and prioritize those with high predicted deleteriousness and mapping to candidate genes (immunity genes,cardiac genes).Candidate variants/genes will be further explored in an international validation cohort and by functional studies using a mice model phenocopying ICI-myocarditis condition.

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

Secondary Outcomes (17)

• Build a polygenic risk score (PRS) based on common variants to discriminate ICIM vs ICI-controls.

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

• Study the impact of age, sex, type of cancer, type of immunotherapies, and race on the penetrance of identified risk-allele associated with ICI myocarditis

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

• Study the impact of age, sex, type of cancer, type of immunotherapies, and race on the penetrance of identified risk-allele associated with ICI myocarditis

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

• Study the impact of age, sex, type of cancer, type of immunotherapies, and race on the penetrance of identified risk-allele associated with ICI myocarditis

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

• Calculation of the diagnostic properties of any relevant SNV/PRS associated with ICI myocarditis vs. initially suspected and subsequently refuted ICI-myocarditis

  Baseline before ICI start and one follow-up point between 3 to 6 months after ICI

Study Arms (3)

ICI-tolerant patients without suspicion of myotoxicity (Controls)

300 Patients on ICI since at least 3 months with a minimum of 2 ICI doses received having no appearance (as compared to baseline known pre-ICI) of new cardio-muscular symptoms or ECG abnormality or wall motion abnormality or troponin-T increase (above Upper Limit of Normal if normal prior to ICI start, or over twice its troponin-T baseline value if abnormal before ICI start)

Patients with refuted suspicion of ICI-myocarditis (controls)

100 Cancer patients treated with ICI and with definite ICI-induced myocarditis according to last updated diagnostic criteria's

ICI-Myocarditis Cases (Cases)

100 Cancer patients treated with ICI admitted for a suspicion of ICI-myocarditis subsequently infirmed

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Adult cancer patients treated by immune checkpoint inhibitors

You may qualify if:

• Cancer patients on ICI since at least 3 months with a minimum of 2 ICI doses received having no appearance (as compared to baseline known pre-ICI) of a new cardio-muscular symptoms or ECG abnormality or WMA or troponin-T increase (above ULN if normal prior to ICI start, or over twice its troponin-T baseline value if abnormal before ICI start).
• Signature of informed consent before any trial procedure from the patient
• Patients covered by social security regimen (excepting AME).

You may not qualify if:

• Age \<18 years of age.
• Pregnant or breast-feeding women
• People under legal protection measure (safeguard measures)
• Patients with a contraindication to MRI (claustrophobia, some wearing equipment with magnetic properties: pacemaker, ferromagnetic equipment, etc.)
• Intolerance to gadolinium, or severe renal insufficiency (GFR\<30 ml/min/1.73 m2).
• Of note, the other groups of patients needed to complete this study; i.e the patients with refuted suspicion of ICI-myocarditis who will serve as controls, and the patients with ICI-myocarditis (cases) are included in another protocol (NCT05454527)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Pitié Salpêtrière

Paris, 75013, France

RECRUITING

MeSH Terms

Conditions

Myocarditis; Myositis

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Joe Elie SALEM, Pr

  Assitance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joe Elie SALEM, Pr

CONTACT

01 42 17 85 35; joe-elie.salem@aphp.fr

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2024
• First Posted: December 16, 2024
• Study Start: September 23, 2025
• Primary Completion (Estimated): January 20, 2028
• Study Completion (Estimated): July 20, 2028
• Last Updated: November 21, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (1)