A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

Abstract

Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

Graphical abstract

Figure 1.

Phase 2a study schema of CD24Fc for GVHD prevention. Two ascending single-dose cohorts and a multidose cohort. BM, bone marrow; PBSC, peripheral blood stem cell.

Figure 2.

Mean (standard deviation) plasma CD24Fc concentration (ng/mL) vs time on a semilogarithmic scale, PK population.^aRegimen (infusion): 480, 240, and 240 mg on days −1, 14, and 28, respectively.

Figure 3.

Kaplan-Meier plot of grade 3 to 4 acute GFS through day 180. (A) Escalation-phase cohorts (pooled CD24Fc and placebo); (B) expansion cohort/matched controls. Follow-up was censored for 4 participants who experienced relapse of primary disease before day 180.

Figure 4.

DAMP (HMGB1) levels of participants (CD24Fc multidose, n = 12) in the open-label expansion cohort. Plasma samples obtained on day –7 (±2 days, preconditioning), day –1 (postconditioning, pretreatment), and day 28 (±2 days, post-HSCT, posttreatment). ∗P < .05; Wilcoxon signed-rank test (GraphPad Prism 8.0). SE, standard error.