AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS

Study Overview
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Brief Summary
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Immune-checkpoint-inhibitors (ICI) have revolutionized treatment for 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 are 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 every week) 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
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Immune-checkpoint-inhibitors (ICI) have revolutionized treatment for 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 are 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 rapid 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. 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 every week) 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.

Official Title
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AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS

Conditions
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Myocarditis

Intervention / Treatment
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* Drug: Abatacept 250 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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 Exclusion Criteria: 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 Being treated with abatacept or belatacept within 3 months prior to inclusion 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A-10mg/kg<br>Patients in arm A will receive doses of 10 mg/kg of Abatacept | Drug: Abatacept 250 MG<br>* 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.<br>* Other names: ORENCIA® BMS;|
| Experimental: B-20mg/kg<br>Patients in arm B will receive doses of 20 mg/kg of Abatacept | Drug: Abatacept 250 MG<br>* 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.<br>* Other names: ORENCIA® BMS;|
| Experimental: C-25mg/kg<br>Patients in arm C will receive doses of 25 mg/kg of Abatacept | Drug: Abatacept 250 MG<br>* 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.<br>* Other names: ORENCIA® BMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80% | CD86RO will be assessed versus baseline levels by isolating circulating monocytes by flux cytometry. A patient will be considered with a 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. | one hour before abatacept administration (Baseline) | 
| Proportion of patients with circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80% | CD86RO will be assessed versus baseline levels by isolating circulating monocytes by flux cytometry. A patient will be considered with a 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. | once 1 to 3 hours after the first administration, 2nd and 3rd abatacept dose. | 
| Proportion of patients with circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80% | CD86RO will be assessed versus baseline levels by isolating circulating monocytes by flux cytometry. A patient will be considered with a 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. | once 24 to 72 hours after the first administration, 2nd and 3rd abatacept dose | 
| Proportion of patients with circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80% | CD86RO will be assessed versus baseline levels by isolating circulating monocytes by flux cytometry. A patient will be considered with a 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. | at Day 21 after the first administration of abatacept | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantification of proxies reflecting the resolution of systemic immune activation | % of regulator T-cells CTLA4+ will be assessed versus baseline levels. In case of additional doses of abatacept, it will also be additionally measured one hour before and one to three hours after each dose of abatacept. | one hour before abatacept treatment (Baseline), once 1 to 3 hours after, and once 24 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 | Levels of pro and anti-inflammatory cytokines will be assessed versus baseline levels. In case of additional doses of abatacept, it will also be additionally measured one hour before and one to three hours after each dose of abatacept. | one hour before abatacept treatment (Baseline), once 1 to 3 hours after, and once 24 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 | C-reactive protein levels will be assessed versus baseline levels. In case of additional doses of abatacept, it will also be additionally measured one hour before and one to three hours after each dose of abatacept. | one hour before abatacept treatment (Baseline), once 1 to 3 hours after, and once 24 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 | % of circulating monocytes expressing PDL1 will be assessed versus baseline levels. In case of additional doses of abatacept, it will also be additionally measured one hour before and one to three hours after each dose of abatacept. | one hour before abatacept treatment (Baseline), once 1 to 3 hours after, and once 24 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 | % of circulating T-cells expressing PD1 will be assessed versus baseline levels. In case of additional doses of abatacept, it will also be additionally measured one hour before and one to three hours after each dose of abatacept. | one hour before abatacept treatment (Baseline), once 1 to 3 hours after, and once 24 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 | Quantification of the corticosteroid decrease kinetics (total cumulative dose) | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of systemic immune activation | Quantification of the proportion of patients for whom it was necessary to add other immunosuppressants in addition to glucocorticoids to control the disease | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | Incidence of heart failure (defined as left-ventricular drop below 50%) | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | Incidence of life-threatening cardiac arrhythmias (defined a sustained >30 seconds ventricular tachycardia epidose, ventricular fibrillation, cardiac arrest, sinus arrest >4 seconds and complete atrio-ventricular block). | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | troponin-T and -I maximal value | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | Area under the curve of troponin levels | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | Creatine Kinase level | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | NT-proBNP | Between Day 0 and Day 90 | 
| Quantification of proxies reflecting the resolution of myocarditis | left ventricular ejection fraction by echocardiography | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the resolution of myocarditis | Cardiac inflammation and myocardial edema quantification | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the resolution of myocarditis | Arrhythmias and ventricular conductive disorders quantified on electrocardiographic Holter acquisitions | At admission, Day 5, Day 14, Day 21, Day 90 and then every 3 months up to one year | 
| Quantification of proxies reflecting the resolution of myocarditis | Humoral autoimmunity against the myocardium or the muscles (anti-troponin I and T, anti-myosin, anti-muscle specific kinases (musK), anti-acetylcholine receptor antibodies). | At admission, Day 5, Day 14, Day 21, Day 90 and then every 3 months up to one year | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: electromyogram | Presence/absence of myogenic syndrome (0/1) Presence/absence of diaphragmatic nerve dysfunction (0/1 Presence/absence of decrement on assessment of neuromuscular dysfunction (0/1) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: capnography. | Number of significant hypoxemic episodes | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: capnography. | Proportion of time with abnormal CO2 (%) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: capnography. | Maximum C02 (mmHg) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: functional respiratory exploration. | Presence/absence of restrictive syndrome (0/1) Presence/absence of sign of diaphragmatic failure (0/1) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: functional respiratory exploration. | Maximal/minimal Inspiratory Pressure (mmHg) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Quantification of proxies reflecting the involvement and resolution of any associated myositis: diaphragmatic MRI and echography. | Excursion of the right diaphragmatic border (mm) Excursion of the left diaphragmatic border (mm) | These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration. | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of the volume of distribution (Liter). In case of additional doses of abatacept, this proxy will also be additionally measured one hour before and one to three hours after each dose of abatacept. | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of terminal half-life (days). In case of additional doses of abatacept, this proxy will also be additionally measured one hour before and one to three hours after each dose of abatacept. | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of clearance (ml/min/kg). In case of additional doses of abatacept, this proxy will also be additionally measured one hour before and one to three hours after each dose of abatacept | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of maximum concentration of circulating abatacept (Cmax, µg/ml). In case of additional doses of abatacept, this proxy will also be additionally measured one hour before and one to three hours after each dose of abatacept | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of residual concentration of circulating abatacept (Cmin). In case of additional doses of abatacept, this proxy will also be additionally measured one hour before and one to three hours after each dose of abatacept | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis with determination of time to Cmax (hours). In case of additional doses of abatacept, these proxies will also be additionally measured one hour before and one to three hours after each dose of abatacept | The three first months after abatacept administration | 
| Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis | Modelling of the 50% median effective concentration (µg/ml) of abatacept to saturate CD86 receptor on circulating monocytes (%) and to normalize troponin levels (ng/ml). In case of additional doses of abatacept, these proxies will also be additionally measured one hour before and one to three hours after each dose of abatacept | The three first months after abatacept administration | 
| Quantification of tumor progression by appropriate examination depending on the tumor type (e.g. CT-scan for lung or renal cancer) using the best monitoring work-up used in standard of care. |  | The imaging modalities will be assessed at least once as soon as possible after admission, after 3 months and one year after abatacept start. | 
| Quantification of the number and severity (in particular fatal) of adverse events, in particular infectious, according to the CTCAE v5.0 classification. | A Full clinical examination searching for any ongoing infection before starting treatment and active clinical monitoring of any sign of new infection during the treatment course and for 1 year. The biological monitoring will include with a blood PCR seeking for CMV reactivation weekly for 4 weeks and then at 3 months and one year (in patients carrying a positive serology for CMV); as well as a blood next generation sequencing seeking for pathogens will be assessed at least once as soon as possible after admission, then at day 14, 3 months and one year after the first abatacept administration. | Full clinical examination : Before starting treatment, during the treatment course and during 1 year / Active clinical monitoring during the treatment course and for 1 year / Biological monitoring : During the first 4 weeks, at 3 months and one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocarditis, Immune-checkpoint-inhibitors (ICI), ICI-induced myocarditis, immune-related adverse events, Abatacept, Dose-finding