AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS

NCT ID: NCT05195645

Last Updated: 2024-12-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-04
• Study Completion Date: 2025-09-15

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.

Detailed Description

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. Other severe irAEs are pneumonitis, hepatitis and neuromyotoxicities (myositis, myasthenia gravis-like syndrome) with death rates of 20-25%. Co-occurrence of irAEs affecting multiple organs is frequent (30% for myocarditis and myositis) as they share underlying mechanisms with macrophages and cytotoxic T-cell infiltrates leading to organ destruction.

While rigorous studies for the treatment of irAEs are lacking, consensus guidelines recommend treatment with high-dose corticosteroids with progressive tapering and withholding ICI. When symptoms and biological markers do not improve, other immunosuppressive drugs (mycophenolate-mofetil, methotrexate, cyclosporine, cyclophosphamide, azathioprine, antithymocyte globulin, infliximab, tocilizumab, and rituximab) can be considered, depending on organs affected. Intravenous immunoglobulin or plasmapheresis can also be considered. In patients developing myocarditis, available therapeutics produce poor results and the fatality rate (40-50%) has stagnated between 2014-2019 despite increasing glucocorticoids use. No treatment has been shown to improve this situation. Thus, better reversal agents' strategies are urgently needed in the context of the increasing use of ICI and of associated irAEs. Abatacept and belatacept (CTLA4-immunoglobulin fusion proteins) have very promising properties: they inhibit CD80/CD86 mediated T-cell co-stimulation at the level of dendritic-cells, thereby abrogating activation of the T-cells upstream of the CTLA4 and PD1/PDL1 pathways. "CTLA4 agonists" leads to global T-cell anergy with limited off-target effects, and specifically reverse ICI-activated pathways.

Abatacept is currently indicated in rheumatological disorders such as rheumatoid arthritis and belatacept is indicated in kidney rejection transplantation prophylaxis. In these latter indications, the circulating monocytes CD86 receptor occupancy (CD86RO) by "CTLA4 agonists" is a relevant pharmacodynamic biomarker of their clinical activity. The target CD86RO cut-off should be over 80%.

Confirming the rationale for "CTLA4 agonists" use in ICI-myocarditis, the investigators recently showed that abatacept was able to alleviate fatal myocarditis in CTLA4/PD1 genetic knock-out mice model. Finally, this group recently described the first cases of glucocorticoid-refractory myocarditis induced by nivolumab (anti-PD1) which resolved after treatment with abatacept. This success prompted the investigators to treat over 15 ICI-myocarditis patients in their institution and several other teams to use abatacept in ICI-induced myocarditis with encouraging results. Though, in their experience, initial doses of abatacept needed to promptly reach CD86RO≥80% in ICI-myocarditis setting were much higher than those needed in its usual indications. Due to abatacept slow time to onset, combination with ruxolitinib (a JAK inhibitor) on top of corticosteroids was also proposed in ICI myocarditis management with very promising results (ICI-myotoxicity related mortality dropped from 60% on corticosteroids + 2nd line abatacept to 3% in 1st line abatacept + ruxolitinib + corticosteroids (https://doi.org/10.1158/2159-8290.CD-22-1180).

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.

Abatacept will be added to the standard of care of these severe ICI myocarditis patients, which include preferentially prednisone and ruxolitinib, tapered as a function of the bio-clinical evolution of ICI-myocarditis.

Conditions

Myocarditis

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

A-10mg/kg

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

Group Type: EXPERIMENTAL

Abatacept 250 MG

Intervention Type: 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.

B-20mg/kg

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

Group Type: EXPERIMENTAL

Abatacept 250 MG

Intervention Type: 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.

C-25mg/kg

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

Group Type: EXPERIMENTAL

Abatacept 250 MG

Intervention Type: 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.

Interventions

Abatacept 250 MG

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.

Intervention Type: DRUG

Other Intervention Names

ORENCIA® BMS

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years old

2. Weight ≥ 40 kg and ≤ 125 kg

3. 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)

4. 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)

5. 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.

6. Signature of informed consent before any trial procedure from the patient or legal representative or the close relative

7. Patients covered by social security regimen (excepting AME)

8. Withhold of ICI

Exclusion Criteria

1. Untreated and/or uncontrolled bacterial, fungal, or viral infection

2. Pregnancy, breast-feeding or planning to become pregnant during the study period

3. For women of childbearing age, lack of effective contraception throughout the duration of participation in the study

4. Being treated with abatacept or belatacept within 3 months prior to inclusion

5. Known hypersensitivity to abatacept or belatacept

6. Being treated with anti-thymoglobulin, or alemtuzumab within 6 weeks of the first scheduled dose of abatacept

7. Patient participating to another interventional study (RIPH 1 only)

8. People under legal protection measure (tutorship, curatorship or safeguard measures)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joe-Elie SALEM, Pr

Role: STUDY_DIRECTOR

Pitie Salpetriere Hospital , APHP

Locations

Hôpital Pitié Salpêtrière

Paris, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 39743436 (View on PubMed)

Other Identifiers

APHP210303

Identifier Type: -

Identifier Source: org_study_id