CLINICAL TRIAL / NCT05335928
Abatacept in Immune Checkpoint Inhibitor Myocarditis
- Interventional
- Recruiting
- NCT05335928
AbatacepT foR ImmUne Checkpoint Inhibitor Associated Myocarditis (ATRIUM): A Phase 3, Investigator-Initiated, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept in ICI Myocarditis
The primary aim is to test whether abatacept, as compared to placebo, is associated with a reduction in major adverse cardiac events (MACE) among participants hospitalized with myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or incident heart failure.
This investigator-initiated randomized trial is being conducted to test whether
abatacept, as compared to placebo, is associated with a reduction in MACE among
participants who develop myocarditis after treatment with an ICI. Immune checkpoint
inhibitors leverage the immune system to treat a wide variety of cancers. Myocarditis is
an uncommon immune related adverse event (irAE) secondary to treatment with an ICI. The
guideline recommended treatment for ICI myocarditis is cessation of the ICI and
administration of corticosteroids. However, despite administration of corticosteroids,
the rate of MACE with ICI myocarditis is high. Data from multiple independent
international cohorts have shown that the rate of MACE with ICI myocarditis despite
administration of corticosteroids ranges from 25-50%.For comparison, the rate of MACE
with myocarditis unrelated to an ICI is <5%.
Abatacept is a selective co-stimulation modulator that inhibits T cell (T lymphocyte)
activation by binding to CD80 and CD86, thereby blocking its interaction with CD28. This
interaction provides a costimulatory signal necessary for full activation of T
lymphocytes. In animal studies of ICI myocarditis, the administration of abatacept led to
a reduction in cardiac immune activation and an increase in survival. In retrospective
unpublished clinical data, the administration of abatacept to participants with ICI
myocarditis on corticosteroids was associated with a reduction in risk of MACE. There are
no prospective studies testing whether abatacept is effective among participants with ICI
myocarditis. Therefore, the primary aim of this trial is to test in a randomized
double-blind placebo-controlled study whether abatacept, administered concurrently with
corticosteroids, is associated with a reduction in MACE among participants with recently
diagnosed ICI myocarditis
Gender
All
Age Group
18 Years and up
Accepting Healthy Volunteers
No
Inclusion Criteria:
1. Must have provided informed consent in a manner approved by the Investigator's
Institutional Review Board (IRB) prior to any study-related procedure being
performed. If a participant is unable to provide informed consent due to his/her
medical condition, the participant's legally authorized representative may consent
on behalf of the study participant, as permitted by local law and institutional
Standard Operating Procedures;
2. Aged greater than or equal to 18 years at the time of informed consent;
3. Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as
administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis),
alone or in combination with other cancer therapies (i.e. chemotherapy, radiation
therapy or targeted therapy). The FDA-approved ICI could be given as part of a
clinical trial but not in combination with a new investigational agent which may
cause myocarditis;
4. A diagnosis of myocarditis.
5. Hospitalized at the time of randomization;
6. On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000
mg of solumedrol per day for myocarditis within 24 hours of first administration of
study drug;
7. Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial
injury will be defined as an institutional troponin (either conventional or
high-sensitivity troponin I or T, using the standard institutional assay) with a
value that is ≥5 times the upper limit of the reference standard normal for that
institution. The troponin assay may be adjusted based on sex depending on
institutional standards. This value of troponin of ≥5 times above the institutional
upper limits of normal value must be noted within 10 days prior to potential
randomization. The 10-day period can be in the outpatient or inpatient setting. For
example, a participant with a troponin value that on one occasion was ≥5 times the
upper limits of institutional normal in the 10-day window prior to potential
randomization (whether in the inpatient or outpatient setting), but later decreases
below that threshold, typically due to starting corticosteroids, would still be
considered eligible;
8. The following laboratory parameters, not older than 48 hours at the time of
randomization, and measured as part of usual care:
- Total white blood cell (WBC) count >2,500/μl
- Absolute neutrophil count (ANC) >1,500/μL
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times
the upper limit of the institutional normal ranges;
9. Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized)
must have a negative highly sensitive urine or serum pregnancy test prior to
randomization. Participating women of childbearing potential must be willing to
consistently use effective methods of contraception from screening until at least 90
days after administration of the last dose of study drug. Participating men must
also be willing to consistently use effective methods of contraception from
screening until at least 90 days after administration of the last dose of study
drug; and
10. Must be willing and able to abide by all study requirements and restrictions.
Exclusion Criteria:
1. Must not have experienced any of the following (as defined in the section on the
primary endpoint) in the 30-day period prior to randomization:
- A sudden cardiac arrest
- Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II
second degree atrioventricular block or third degree (complete)
atrio-ventricular (AV) block, for which an intervention with a temporary or
permanent pacemaker is completed or recommended).
- A significant tachyarrhythmia (ventricular fibrillation of any duration or
sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a
ventricular tachyarrhythmia requiring intervention.
2. Recent (≤2 month) exposure to abatacept or belatacept.
3. Concurrent or recent (≤2 month) use of the following non-corticosteroid
immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT
inhibitors (including but not limited to upadacitinib, tofacitinib, baricitinib, and
filgotinib), tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and
plasma exchange. The use of intravenous immunoglobulin is permitted prior to
randomization and during study treatment.
4. Currently enrolled in another interventional study utilizing systemic agents for the
management of ICI-related toxicities.
5. Female who is pregnant, breastfeeding, or is considering becoming pregnant during
the study or for approximately 90 days after the last dose of study drug.
6. Male who is considering fathering a child or donating sperm during the study or for
approximately 30 days after the last dose of study drug.
7. Any active, chronic, or recurrent viral infection that, based on the investigator's
clinical assessment, makes the participant an unsuitable candidate for the study.
These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or
disseminated (even a single episode) herpes zoster, and disseminated (even a single
episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface
antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic
acid (DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core
antibody (HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA)
detectable in any participant with anti-HCV antibody (HCV Ab). Patients with active
Covid-19 infection will be excluded. This is defined as the period of ongoing
symptoms in the setting of a positive Covid-19 test, or until 10 days after symptom
onset and after resolution of fever for at least 24 hours, without the use of
fever-reducing medications.
8. Known active tuberculosis (TB), history of incompletely treated TB, suspected or
known extrapulmonary TB, suspected or known systemic bacterial or fungal infections;
9. Receipt of any live vaccine within four weeks prior to the first dose of study drug,
or expected need of live vaccination during study participation including at least
90 days after the last dose of IV study drug.
10. Any medical condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or interpretation of the study results, or
that would, in the opinion of the Investigator, increase the risk of the participant
by participating in the study.
11. Any factors that, in the Investigator's opinion, are likely to interfere with study
procedures, such as history of noncompliance with scheduled appointments.