Clinical trial NCT05195645: AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS
Official title: AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Myocarditis
Keywords: Myocarditis
Immune-checkpoint-inhibitors (ICI)
ICI-induced myocarditis
immune-related adverse events
Abatacept
Dose-finding
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-01-19
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Proportion of patients with an adequate circulating monocytes CD86 receptor occupancy (CD86RO) saturation ≥ 80%
timeFrame: 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:
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: 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
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: 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
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: 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
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: 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
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: 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
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 90
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 21
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 90
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 21
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 90
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 21
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 90
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 21
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 90
measure: Quantification of proxies reflecting the resolution of systemic immune activation
timeFrame: Between Day 0 and Day 21
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: Between Day 0 and Day 21, and Day 90
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: At admission, Day 5, Day 14, Day 21, Day 90 and then every 3 months up to one year
measure: Quantification of proxies reflecting the resolution of myocarditis
timeFrame: At admission, Day 21, Day 90, 6 months and one year
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis:
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Quantification of proxies reflecting the involvement and resolution of any associated myositis:
timeFrame: These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after the first abatacept administration.
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Throughout the study completion (up to one year after randomization)
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: Abatacept, CD86RO and troponin-T blood levels assessed minimum at baseline (1-3h before abatacept) and once 1-3h after, and 12-72h after 1st, 2nd, 3rd and extra abatacept doses, then every 10days up to day90, and then every 3months up to 1year.
measure: Pharmacokinetic/pharmacodynamic (PK-PD) modelling of abatacept in ICI-myocarditis
timeFrame: ADA will be searched at inclusion (before 1st abatacept intake), and then at day 21, 3 months and 6 months after randomization
measure: Quantification of tumor progression
timeFrame: The imaging modalities will be assessed at least once as soon as possible after admission, after 3 months and one year after abatacept start.
measure: Quantification of tumor progression
timeFrame: Progression free survival rate at 90days, 6 months and 12 months
measure: Quantification of the number and severity (in particular fatal) of adverse events, in particular infectious, according to the CTCAE v5.0 classification.
timeFrame: 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
measure: Overall survival
timeFrame: Between Day 0 and 1 month, 3 months, 6 months and 12 months
measure: Overall survival
timeFrame: Between Day 0, and 3 months, 6 months and 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière
Study officials:
affiliation: Pitie Salpetriere Hospital , APHP
name: Joe-Elie SALEM, Pr
role: STUDY_DIRECTOR
References: