Euplagia-1: A Phase 1/2 Trial of GLPG5201, a Fresh Stem-like Early Memory CD19 CAR T-Cell Therapy with a 7-Day Vein-to-Vein Time, in Patients with Relapsed/Refractory CLL and RT

Background: Despite developments in treating hematological malignancies, survival remains poor for patients (pts) with double-refractory CLL and Richter transformation (RT), and new treatment options are needed. Achieving complete remission in these pts can lead to long-term benefits but remains rare. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have shown promise, but T-cell dysfunction caused by longstanding CLL may hamper efficacy. CAR T-cell efficacy relies in part on preserving early T-cell phenotypes during ex vivo manufacturing and on robust in vivo expansion. Efficacy may be improved by short vein-to-vein time and elimination of the need for cryopreservation. Here, we present updated Phase (Ph)1 results from the EUPLAGIA-1 study of GLPG5201, a fresh, stem-like early memory phenotype CD19 CAR T-cell therapy manufactured using a rapid decentralized platform enabling a 7-day vein-to-vein time.

Methods: EUPLAGIA-1 (CTIS: 2022-501686-47-00) is an ongoing Ph1/2 study of GLPG5201 in pts with R/R CLL (≥2 prior therapy lines) and RT. The Ph1 primary objective is safety. Secondary objectives include manufacturing feasibility, efficacy, and pharmacokinetics.

Results: As of February 21, 2024, 15 pts were enrolled at 1 institution (6/15 with R/R CLL and 9/15 with RT). Median (range) age was 66 (50-74) years; 10/15 pts were male. For pts with CLL, median (range) number of prior therapies was 4 (2-10), and all pts were double refractory to BTKi and BCL2i therapy. For pts with RT, median (range) number of prior therapies was 3 (3-5); all pts with RT received CLL-directed therapy prior to RT diagnosis and 8/9 pts received chemo(immuno)therapy after RT diagnosis; 1 pt with RT received an allogeneic stem cell transplant and 1 pt was treatment naive for RT.

GLPG5201 was administered as a fresh infusion with a median (range) 7-day vein-to-vein time (7-14). Six pts received dose level (DL)1 and 9 received DL2 (35x10⁶ and 100x10⁶ CAR⁺ T cells, respectively). The proportion of early T-cell phenotypes (naive/stem cell memory and central memory) was higher in the final product (FP) compared with leukapheresis starting material (SM): CD4⁺ T cells median (range) change +23.6% (-17.9 to 39.3), with an increase observed in 10/13 pts; CD8⁺ T cells median (range) change +50.8% (7.6 to 73.3), with an increase observed in 13/13 pts. Moreover, the ratio of CD4⁺:CD8⁺ CAR T cells increased in the FP. Robust CAR T-cell expansion was observed by qPCR in all pts, independent of DL. Peak expansion and exposure were comparable between pts with CLL and RT. Median time to peak expansion was 14 days for both subgroups. Persistence was durable and could be detected in peripheral blood up to 15 months post-infusion. Upon infusion, abundance of CD4⁺ and CD8⁺ naive/stem cell memory CAR T cells in the FP positively correlated with in vivo CAR T-cell exposure (AUC_d0-28) (Spearman rank correlation [95% CI] for CD4⁺: 0.67 [0.23, 0.91], and for CD8⁺: 0.80 [0.50, 0.93]).

Most Grade ≥3 treatment-emergent adverse events (reported up to 14 weeks post-infusion) were hematological. No Grade ≥3 CRS or any-grade ICANS were observed; CRS Grade 1-2 occurred in 8 (53%) pts. Two deaths occurred in pts with RT: 1 event of cytomegalovirus colitis 14.5 months post-infusion in a pt with complete response (CR), and 1 death due to disease progression 110 days post-infusion.

At a median (range) follow-up of 8.8 (0.9 to 21.0) months, 13/15 efficacy-evaluable pts responded (objective response rate 86.7%; 83.3% for pts receiving DL1 [5/6] and 88.9% for DL2 [8/9]). Three of 13 pts progressed after an initial response; 9/13 (69.2%) pts who responded had ongoing responses at data cutoff. CR was achieved by 10/15 pts (CR rate 66.7%; 50.0% for pts receiving DL1 [3/6] and 77.8% for DL2 [7/9]). Across DL1 and DL2, 8/10 (80.0%) pts who achieved a CR had an ongoing CR. Overall, 12/15 (80.0%) pts remain ongoing in the study for further follow-up.

Conclusions: In this analysis of the ongoing EUPLAGIA-1 study, rapid, fresh decentralized manufactured GLPG5201 showed an increase in stem-like early memory phenotypes versus SM, robust in vivo expansion, and durable persistence. Infusion of fresh, fit GLPG5201 with a 7-day vein-to-vein time led to encouraging efficacy in pts with CLL and RT, and a manageable overall safety profile, with no ICANS or Grade ≥3 CRS.