AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS

NCT05195645 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: APHP210303
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Immune-checkpoint-inhibitors (ICI) have revolutionized treatment for about 20 cancer types. They unleash anti-tumor immune responses. Unfortunately, in 0.36-1.23% of patients, this activation can also lead to lethal immune-related adverse events (irAEs) that can affect any organ. Among those irAEs, ICI-induced myocarditis was the most frequently fatal with death rate reaching 50% in a large case-series of over 100 patients. This study is a dose-finding Phase II trial where 3 abatacept IV regimen (A-10 mg/kg; B-20 mg/kg and C-25 mg/kg at Day0, Day5+/-2, Day14+/-2) will be tested aiming at reaching promptly (after the first dose) and sustainably a CD86RO≥80% during the first 3 weeks of ICI-myocarditis management. The main objective is to find the lowest dose required to achieve a circulating monocytes CD86RO≥80% within the first week of treatment and sustainably over three weeks. The target population is all adult patients with cancer (all cancer types) treated by immune checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4 monotherapies or combination) and presenting drug-induced myocarditis.

Conditions

Myocarditis

Keywords

Myocarditis; Immune-checkpoint-inhibitors (ICI); ICI-induced myocarditis; immune-related adverse events; Abatacept; Dose-finding

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with an adequate circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80%

  A patient will be considered with an adequate CD86RO saturation (≥80%) within the first weeks of treatment if at least three CD86RO assessment are over 80% until Day 21 after the first abatacept administration.

  CD86RO will be assessed versus baseline levels (1 to 3 hours before 1st abatacept administration for baseline) and then, once 1 to 3 hours and 12 to 72 hours after the 1st, 2nd and 3rd abatacept administration, and at Day 21 .

Secondary Outcomes (52)

• Quantification of proxies reflecting the resolution of systemic immune activation

  one to 3 hours before abatacept treatment (Baseline), once 1 to 3 hours after, and once 12 to 72 hours after the first administration, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up

• Quantification of proxies reflecting the resolution of systemic immune activation

  one to 3 hours before abatacept treatment (Baseline), once 1 to 3 hours after, and once 12 to 72 hours after the first administration, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up

• Quantification of proxies reflecting the resolution of systemic immune activation

  one to 3 hours before abatacept treatment (Baseline), once 1 to 3 hours after, and once 12 to 72 hours after the first administration, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up

• Quantification of proxies reflecting the resolution of systemic immune activation

  one to 3 hours before abatacept treatment (Baseline), once 1 to 3 hours after, and once 12 to 72 hours after the first administration, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up

• Quantification of proxies reflecting the resolution of systemic immune activation

  one to 3 hours before abatacept treatment (Baseline), once 1 to 3 hours after, and once 12 to 72 hours after the first administration, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up

Study Arms (3)

A-10mg/kg

EXPERIMENTAL

Patients in arm A will receive doses of 10 mg/kg of Abatacept

Drug: Abatacept 250 MG

B-20mg/kg

EXPERIMENTAL

Patients in arm B will receive doses of 20 mg/kg of Abatacept

Drug: Abatacept 250 MG

C-25mg/kg

EXPERIMENTAL

Patients in arm C will receive doses of 25 mg/kg of Abatacept

Drug: Abatacept 250 MG

Interventions

Abatacept 250 MG DRUG

Abatacept will be administered by intravenous injection over 1h15 to 2h30 on D1, D5+/-2 and D14+/-2 at 10mg/kg (arm A), or 20mg/kg (arm B) or 25mg/kg (arm C) depending on the randomization (max 3 000 mg per administration). Starting Day 21 (after evaluation of the primary outcome), other injection of abatacept may be given (D22 at D90) with dosage (10 or 20mg/kg max) decided by the treating physician (max 2 500 mg per administration) as a function of the relapse or not of the ICI myocarditis after immunosuppressant therapeutics tapering. After day 21, the administrations will be carried out in open but the blind administration 1 to 3 (D1 to D21) will be kept.

Also known as: ORENCIA® BMS

A-10mg/kg; B-20mg/kg; C-25mg/kg

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years old
• Weight ≥ 40 kg and ≤ 125 kg
• Patients treated with ICI immunotherapy (monotherapy or combination), including anti-PD1, anti-PDL1, anti-CTLA4; and including any type of cancer (even those in which ICI is not currently approved by regulatory)
• Definite, probable or possible ICI-induced myocarditis according to the diagnostic criteria of the most recent expert consensus recommendations (e.g27, to be updated with any new recommendations to be published)
• Severe or corticosteroid-resistant ICI-myocarditis:
• Severe ICI-myocarditis is defined either 1/ by the appearance of an alteration of the LVEF\<50% or a wall motion kinetics abnormality, or 2/ by the appearance of ventricular tachycardias or high-grade conductive disorders (atrioventricular block grade 2 or 3) or 3/ by the association with myasthenia gravis-like-syndrome (diplopia, ptosis, diaphragmatic dysfunction, dysarthria, dysphonia, dysphagia) or 4/ by troponin-T levels above 32 times the upper limit of the normal (a population at very high-risk \~75% of major cardiomuscular events in the month following initial presentation, cf. Circulation. 2023 Aug 8;148(6):473-486).
• Corticosteroid-resistant ICI-myocarditis is defined by the absence of decrease in troponin levels or the appearance/persistence of severity criteria despite receiving prednisone dose ≥0.5 mg/kg/day for ≥2 days.
• Signature of informed consent before any trial procedure from the patient or legal representative or the close relative
• Patients covered by social security regimen (excepting AME)
• Withhold of ICI

You may not qualify if:

• Untreated and/or uncontrolled bacterial, fungal, or viral infection
• Pregnancy, breast-feeding or planning to become pregnant during the study period
• For women of childbearing age, lack of effective contraception throughout the duration of participation in the study
• Known hypersensitivity to abatacept or belatacept
• Being treated with anti-thymoglobulin, or alemtuzumab within 6 weeks of the first scheduled dose of abatacept
• Patient participating to another interventional study (RIPH 1 only)
• People under legal protection measure (tutorship, curatorship or safeguard measures)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Pitié Salpêtrière

Paris, 75013, France

Location

Related Publications (1)

• Salem JE, Ederhy S, Belin L, Zahr N, Tubach F, Procureur A, Allenbach Y, Rosenzwjag M, Bretagne M. Abatacept dose-finding phase II triaL for immune checkpoint inhibitors myocarditis (ACHLYS) trial design. Arch Cardiovasc Dis. 2025 Feb;118(2):106-115. doi: 10.1016/j.acvd.2024.12.005. Epub 2024 Dec 20.

  PMID: 39743436 DERIVED

MeSH Terms

Conditions

Myocarditis

Interventions

Abatacept

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins

Study Officials

• Joe-Elie SALEM, Pr

  Pitie Salpetriere Hospital , APHP

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2021
• First Posted: January 19, 2022
• Study Start: October 4, 2022
• Primary Completion: March 5, 2024
• Study Completion: September 15, 2025
• Last Updated: December 13, 2024

Record last verified: 2024-12

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)