GLPG5201: CD19 CAR-T in relapsed and refractory chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin. CLL affects B-cells in the blood and bone marrow.1 Richter Transformation (RT) is an uncommon clinicopathological condition observed in patients with CLL. It is characterized by the sudden transformation of the CLL into a significantly more aggressive form of large cell lymphoma and occurs in approximately 2-10% of all CLL patients. CLL usually follows an indolent course and is an incurable disease. Patients who develop relapsed and refractory disease and become resistant to new agents have a dismal prognosis and a high unmet medical need for new therapeutic options such as CAR-T cells. With estimated incidence of 4.7 new cases per 100,000 individuals, CLL is the most prevalent lymphoid malignancy and is the most common adult leukemia in the US and in Europe.2 The annual incidence of patients with RT has been estimated at 1,900 new patients in the US and 2,000 in the EU5.3
GLPG5201 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as a single fixed intravenous dose. The safety, efficacy and feasibility of point-of-care manufactured GLPG5201 are currently being evaluated in the EUPLAGIA-1 Phase 1/2, open-label, multicenter study in patients with rrCLL and rrSLL (small lymphocytic lymphoma), with or without RT.
Patients with CD19 rrCLL or rrSLL with >2 lines of therapy are eligible to participate, and patients with RT are eligible, regardless of prior therapy. The primary objective of the Phase 1 part of the study is to evaluate safety and determine the recommended dose for the Phase 2 part of the study. The dose levels that are evaluated in the Phase 1 part of the study are 35x106 (DL1), 100x106 (DL2), and 300x106 (DL3) CAR+ viable T cells.
The primary objective of the Phase 2 part of the study is to assess the ORR, and the secondary objectives include the analysis of the CRR, duration of response, progression free survival, overall survival, safety pharmacokinetic profile, and feasibility of point-of-care manufacturing.
EUPLAGIA-1 Phase 1/2 study design of GLPG5201 in rrCLL, with or without RT
Baseline characteristics EUPLAGIA-1: heavily pre-treated CLL & RT patient population
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All patients |
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Age, median (range), years |
66 (50-74) |
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Male, n (%) |
10 (67) |
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Disease subtype, n (%) |
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CLL |
6 (40) |
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RT |
9 (60) |
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No. of prior therapy lines, median (range) |
3 (2-10) |
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Prior BTKi, n (%) |
13 (87) |
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Prior venetoclax, n (%) |
12 (80) |
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Prior BTKi and venetoclax, n (%) |
11 (73) |
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Prior allo-HSCT, n (%) |
1 (7) |
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High-risk features(*), n (%) |
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17p deletion |
3/13 (23) |
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TP53 mutated |
6/13 (46) |
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Complex karyotype(**) |
3/6 (50) |
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IGHV unmutated(***) |
13/13 (100) |
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In February 2023, we presented initial encouraging safety and efficacy data (cut-off date: 9 January 2023) from the EUPLAGIA-1 Phase 1 study during a poster session at the EBMT-EHA 5th European CAR-T-cell Meeting in Rotterdam.
As of 6 September 2023, patient recruitment of the Phase 1 dose-finding part of EUPLAGIA-1 had been completed, and 15 patients (6 at dose level 1 (DL1); and 9 at dose level 2 (DL2)) were enrolled, all of whom were diagnosed with rrCLL, and 9 with additional RT. All 15 Phase 1 batches were manufactured at the point-of-care and infused as a single fresh, fit product within a median vein-to-vein time of seven days, with 80% of patients receiving the product in seven days. In December 2023, we presented promising new preliminary data from the Phase 1 dose-finding part of the study during a poster session at the 65th Annual ASH Congress in San Diego. Efficacy data as of day 28 were available for 14 patients; 1 patient did not yet reach the day 28 follow-up visit at the time of the analysis. The results (cut-off date: 6 September 2023) are presented below:
Encouraging interim safety data: EUPLAGIA-1 preliminary Phase 1 data in heavily pretreated patient population
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All patients (N=15) |
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CRS, n (%) |
7 (47) |
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Grade 1/2 |
7 |
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Grade ≥3 |
0 |
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ICANS, n (%) |
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Any grade |
0 |
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Promising clinical activity observed in rrCLL and RT: EUPLAGIA-1 preliminary Phase 1 data in heavily pretreated patient population
*Combined response, iwCLL for CLL patients without RT and Lugano classification for patients with RT. DL1: 35x106 CAR-positive viable T cells, DL2: 100x106 CAR-positive viable T cells. CR, complete response; CRR, CR rate; DL, dose level; ORR, objective response rate; RT, Richter Transformation; PR, partial response; rrCLL, relapsed/refractory chronic lymphocytic leukemia. 1 CLL patient not yet efficacy-evaluable (D28 not reached).
Promising clinical activity observed in RT subset: EUPLAGIA-1 preliminary Phase 1 data in RT patients
*Combined response, iwCLL for patients without RT and Lugano classification for patients with RT. DL1: 35x106 CAR-positive viable T cells, DL2: 100x106 CAR-positive viable T cells. CR, complete response; CRR, CR rate; DL, dose level; ORR, objective response rate; RT, Richter Transformation; PR, partial response; rrCLL, relapsed/refractory chronic lymphocytic leukemia.
- GLPG5201 showed an encouraging safety profile with most TEAEs of Grade 1 or 2, mostly hematological. CRS Grade 1 or 2 was observed in 47% of the patients, and no CRS Grade ≥ 3 or any ICANS were observed. No deaths were reported.
- Overall, 13 of 14 efficacy evaluable patients responded to treatment (Objective Response Rate (ORR) of 93%) and 8 of 14 patients achieved a Complete Response Rate (CRR of 57%). 8 of 9 patients with RT responded to treatment (ORR of 89%) and 6 of 9 RT patients achieved a Complete Response (CRR of 67%). At time of analysis, 10 of 13 of responding patients (77%) were in ongoing response with a median follow-up of 6 months; 2 of 3 patients who progressed after an initial response had confirmed CD19-negative disease.
- On the higher dose level (DL2), 8 of 8 patients responded to treatment (ORR of 100%), 5 of 8 patients achieved a Complete Response (CRR of 63%), and 6 of 6 patients with RT responded to treatment (ORR of 100%).
- DL2 was selected as the recommended dose for the Phase 2 part of the study.
At the annual EBMT-EHA congress in February 2024, we showcased encouraging preliminary translational data regarding the status of the CAR-T cells in the GLPG5201 final product (FP).
A thorough characterization of the collected patient material in the EUPLAGIA-1 trial (10 patients) revealed an increased percentage of ‘early phenotype’ T cells (i.e. TN/SCM and TCM, CD4+ and CD8+) in the final product compared to the starting material (apheresed blood). This was in line with the observed decrease in more differentiated, ‘late phenotype’ T cells (i.e. TEM/EFF, CD4+ and CD8+).
This early phenotype reflects the differentiation status of the cells, which is associated with enhanced functionality and persistence of CAR-T cells after infusion in the patient.
GLPG5201 product characteristics
GLPG5201 enriches frequency of early phenotype (i.e. TN/SCM and TCM) CD4+ and CD8+ CAR-T cells in final drug product compared to T cells in starting material, in tandem with a decrease in TEM/EFF CAR-T cells
Exploratory flow cytometry analysis of T-cell subsets in the apheresis starting material (SM) and final product (FP), showing box plots with first quartile (Q1), median (Q2) and third quartile (Q3), whiskers as well as all the individual datapoints. Med, median.
Similarly to the ATALANTA-1 study, we evaluated the kinetics of expansion of the manufactured CAR-T cells in the patient by measuring the levels of CAR vector copies in blood after infusion.
CAR-T cell expansion and persistence data was available for 13 of 15 patients. Robust expansion was observed in all patients for the dose levels tested with a median time to peak expansion of 14 days.
In 3 out of 4 evaluable patients, we were able to detect the GLPG5201 CAR-T cells up to 9 months post-infusion (cut-off date of 6 September 2023). These findings support the persistence of GLPG5201, which could be an early predictor of durable responses.
Cellular expansion and persistence of GLPG5201
Robust CAR T-cell expansion observed in all patients
DL, dose level; LOQ, limit of quantification.
The EUPLAGIA-1 preliminary safety, efficacy, and translational data presented above suggest that Galapagos’ CAR-T point-of-care manufacturing platform can deliver a fit product in a median vein-to-vein time of only seven days.
1 1Wierda WG. Chronic lymphocytic leukemia/ Small lymphocytic lymphoma fact sheet. In: Foundation LR, editor. 2018: https://www.lymphoma.org/wp-content/uploads/2018/04/LRF_FACTSHEET_CLL_SLL.pdf
2 2Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA: A Cancer Journal for Clinicians. 2021;71(1):7-33. https://www.ncbi.nlm.nih.gov/books/NBK493173
3 3IMARC report, 2023; 2-15% of incidence per Lightning Health literature review; Sigmund AM et al. 2022; Thompson PhA et al. 2022.IMARC report, 2023; 2-15% of incidence per Lightning Health literature review; Sigmund AM et al. 2022; Thompson PhA et al. 2022.