Abatacept dose-finding phase II triaL for immune checkpoint inhibitors myocarditis (ACHLYS) trial design.

Abstract

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a life-threatening adverse drug reaction. Abatacept (a CTLA-4-immunoglobulin fusion protein) has been proposed as a compassionate-use treatment for ICI myocarditis (in combination with corticosteroids and ruxolitinib) but no clinical trial has yet been performed. The abatacept dose can be adjusted using real-time assessment of its target, the CD86 receptor occupancy on circulating monocytes (CD86RO).

Methods: The ACHLYS trial is an ongoing dose-finding, Phase II, randomized, double-blind trial in which three different abatacept doses are being tested, aiming to reach CD86RO≥80% after the first dose and sustainably during the first 3 weeks of ICI myocarditis treatment (primary outcome). Adult patients with cancer presenting severe or corticosteroid-resistant ICI myocarditis have been included. ICI are withheld after inclusion and for the study duration. Abatacept is administered by intravenous injection on Days 1, 5±2 and 14±2 at 10, 20 or 25mg/kg depending on the randomization arm (n=7 per arm) with concomitant ruxolitinib and corticosteroids. After evaluation of the primary outcome on Day 21, complementary injections of abatacept (for≤3 months) and a ruxolitinib/corticosteroids weaning strategy are standardized depending on criteria evaluating resolution of ICI myocarditis severity (troponin T level and clinical assessment). Secondary objectives compare immunological, myocardial and muscular proxies of treatment response between randomization arms, and cancer progression-free and overall survivals up to 1 year.

Conclusion: The ACHLYS trial will define the most appropriate starting dose of abatacept to treat life-threatening ICI myocarditis, in combination with ruxolitinib and corticosteroids.

Clinicaltrials: GOV: NCT05195645.