Abatacept in Immune Checkpoint Inhibitor Myocarditis

Cancer Clinical Trial

— ATRIUM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05335928
• Other study ID #: 2021P003690
• Status: Recruiting
• Phase: Phase 3
• Start date: June 22, 2022
• Est. completion date: April 2027

Study information

• Verified date: September 2023
• Source: Massachusetts General Hospital
• Contact: Hannah K Gilman, MS
• Phone: 6177261019
• Email: hkgilman[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 390
• Est. completion date: April 2027
• Est. primary completion date: November 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cancer
• Myocarditis
• Myocarditis Acute

Intervention

Drug:
• Abatacept plus
Up to 4 study drug infusions at 10 mg/kg, IV Drug: Standard of care Local standard of care per written policies or guidelines Other Name: SoC
• Placebo
Drug: Standard of care Local standard of care per written policies or guidelines Other Name: SoC

Locations

Country	Name	City	State
Canada	McMaster University	Hamilton	Ontario
Canada	University of British Colombia	Vancouver	British Colombia
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins	Baltimore	Maryland
United States	Lehigh Valley Health Network	Bethlehem	Pennsylvania
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina Chapel Hill	Chapel Hill	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Texas Southwestern	Dallas	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Franciscan Health	Indianapolis	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Kentucky	Lexington	Kentucky
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of California Los Angeles	Los Angeles	California
United States	Aurora St Luke's Medical Center	Milwaukee	Wisconsin
United States	University of West Virginia	Morgantown	West Virginia
United States	Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Columbia University Irving Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Allegheny-Singer Research Institution	Pittsburgh	Pennsylvania
United States	Maine Health	Portland	Maine
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Moffitt Cancer Center	Tampa	Florida
United States	MedStar Health Research Institute, Georgetown University	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major adverse cardiac events	The rates of a composite of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure.	6 months
Secondary	The individual components of the primary endpoint.	The rates of the following between groups: cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure	6 months
Secondary	Myocarditis illness severity using a 7-point ordinal severity scale containing each of the individual endpoints in a hierarchical ranking order.	The worst score on a 7-point ordinal myocarditis severity scale during the 6 month period from first study treatment. The 7-point ordinal myocarditis severity scale is as follows with more severe outcomes ranked with a higher number: - No component of the primary endpoint; - Incident heart failure; - Significant bradyarrhythmia; - Significant ventricular tachyarrhythmias; - Cardiogenic shock; - Sudden cardiac arrest; - Cardiovascular death;	6 months
Secondary	The increase in serum troponin levels	The proportion of participants in each group with a >50% increase in serum troponin value at any time during the incident hospitalization and following administration of study drug.	6 months
Secondary	The combination of the rates of the primary outcome plus the proportion of patients with a troponin increase.	The rates of a composite of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure plus the proportion of participants in each group with a >50% increase in serum troponin value at any time during the incident hospitalization and following administration of study drug.	6 months
Secondary	Clinical status at 90 days after first infusion of study drug	Clinical status at visit 6 (day 90) on an ordinal scale with highest being the worst: - Alive and off corticosteroids for myocarditis; - Alive and on corticosteroids (provide dose) for myocarditis; - Alive and on cellcept (provide dose) for myocarditis; - Alive and on both corticosteroids (provide dose) and cellcept (provide dose) for myocarditis; - Dead (cancer, cardiovascular or other).	6 months
Secondary	Clinical status at 6 months after first infusion of study drug	Clinical status at visit 7 (6 months) with the highest being the worst: - Alive and off corticosteroids for myocarditis; - Alive and on corticosteroids (provide dose) for myocarditis; - Alive and on cellcept (provide dose) for myocarditis; - Alive and on both corticosteroids (provide dose) and cellcept (provide dose) for myocarditis; - Dead (cancer, cardiovascular or other).	6 months
Secondary	Fatal and non-fatal DVT and PE	The proportion of patients in each group with a fatal and non-fatal DVT and PE will be compared.	6 months
Secondary	Other immune-related adverse events between the two groups	Rates of other immune-related adverse events between the two groups will be compared.	6 months