Myocarditis Clinical Trial
— ACHLYSOfficial title:
AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS
Verified date | February 2024 |
Source | Assistance Publique - Hôpitaux de Paris |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Active, not recruiting |
Enrollment | 21 |
Est. completion date | September 15, 2025 |
Est. primary completion date | October 7, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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). - 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) |
Country | Name | City | State |
---|---|---|---|
France | Hôpital Pitié Salpêtrière | Paris |
Lead Sponsor | Collaborator |
---|---|
Assistance Publique - Hôpitaux de Paris |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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) | |
Primary | 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. | |
Primary | 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 | |
Primary | 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 | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | Quantification of proxies reflecting the resolution of myocarditis | troponin-T and -I maximal value | Between Day 0 and Day 90 | |
Secondary | Quantification of proxies reflecting the resolution of myocarditis | Area under the curve of troponin levels | Between Day 0 and Day 90 | |
Secondary | Quantification of proxies reflecting the resolution of myocarditis | Creatine Kinase level | Between Day 0 and Day 90 | |
Secondary | Quantification of proxies reflecting the resolution of myocarditis | NT-proBNP | Between Day 0 and Day 90 | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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. | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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. | ||
Secondary | 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 |
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