A phase I/II, multicenter study evaluating the feasibility, safety, and efficacy of point-of-care manufactured GLPG5101 (19CP02) in subjects with relapsed/refractory B-cell non-Hodgkin lymphoma

The primary objective of this phase I/II multicenter study is to evaluate the **safety** of GLPG5101 and determine the recommended Phase 2 doses (RP2Ds) during the Phase I dose-escalation phase. In the Phase II dose expansion phase, the study aims to evaluate the **efficacy** of GLPG5101 in different subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). This is clinically relevant as it seeks to establish a safe and effective treatment regimen for patients with this challenging condition.

Secondary objectives include:

• Evaluating the safety of GLPG5101.
• Assessing the efficacy of GLPG5101.
• Investigating the pharmacokinetics of GLPG5101.
• Exploring the pharmacodynamics of GLPG5101.
• Determining the feasibility of GLPG5101 manufacturing in relapsed/refractory B-cell NHL patients.
• Evaluating health-related Quality of Life (HRQoL) during Phase II.

The clinical trial involves a total of **55 participants** diagnosed with **relapsed/refractory B-cell non-Hodgkin lymphoma**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Participants were selected based on their diagnosis of specific non-Hodgkin lymphoma subtypes, including DLBCL, FL grade 1, 2 or 3A, MZL, MCL, BL, PCNSL, DLBCL-RT, and High-Grade B-cell Lymphoma (HGBL). The trial population is characterized by adequate bone marrow, renal, hepatic, and pulmonary function, and the presence of at least one measurable lesion according to the Lugano classification. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to strict contraceptive measures if of childbearing potential. The trial includes a vulnerable population, ensuring comprehensive safety and efficacy evaluations of the investigational drug GLPG5101.

The clinical trial is designed to evaluate the **safety** and **efficacy** of GLPG5101 (19CP02) in subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. This is a Phase I/II, multicenter study with a randomized, double-blind, controlled design. The trial is expected to run from December 2021 to March 2029. The study is divided into two phases: a Phase I dose-escalation phase to assess safety and determine recommended Phase 2 doses (RP2Ds), and a Phase II dose expansion phase to evaluate efficacy across different non-Hodgkin lymphoma subtypes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and organ function. Following successful screening, participants will receive the investigational product, 19CP02, administered as a **dispersion for infusion** via **intravenous use**. Follow-up visits will be scheduled to monitor the incidence of adverse events, dose-limiting toxicities, and objective response rates, with assessments continuing up to two years post-infusion. The end-of-study visit will conclude the participant's involvement, with data collected on overall survival, progression-free survival, and other secondary endpoints.

The expected length of participant involvement varies, with the primary endpoint for Phase I being assessed until Day 28, and Phase II endpoints evaluated up to two years post-infusion. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or failure to adhere to study protocols. Participants are required to use highly effective contraception methods during the study and for 12 months post-infusion to prevent pregnancy. The trial aims to provide comprehensive data on the therapeutic potential of GLPG5101 in treating relapsed/refractory B-cell non-Hodgkin lymphoma.

The clinical trial involves the administration of the experimental medication **19CP02**, which is a **dispersion for infusion**. This investigational product is designed for **intravenous use** and is being evaluated for its feasibility, safety, and efficacy in subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. The active substance in 19CP02 is a **structurally diverse substance** utilized in **cell therapy**, specifically targeting the **anti-CD19 CAR**. The product is manufactured by CELLPOINT B.V. and is not formulated for pediatric use. The trial is structured in two phases: a Phase I dose-escalation phase to evaluate safety and determine recommended Phase 2 doses, and a Phase II dose expansion phase to assess efficacy across different NHL subtypes.

In this study, 19CP02 is administered as a **dispersion for infusion** via the **intravenous route**. The investigational product is a genetically modified organism (GMO) involving **T cells** and is produced using a **lentivirus** vector. The gene transfer product type is classified as type 3, and the therapy is categorized under advanced therapy type 3. The trial does not include any comparator treatments, placebos, or standard-of-care therapies as part of the study design. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the investigational product GLPG5101 (19CP02) in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Phase II is the **Objective Response (OR)**, which will be evaluated up to two years post-infusion of GLPG5101, using the Lugano Classification or IPCG criteria for Primary Central Nervous System Lymphoma (PCNSL). Secondary endpoints include a comprehensive assessment of the type, frequency, and severity of adverse events (AEs), including those of special interest, and laboratory abnormalities. Additionally, the trial will measure the OR up to two years post-infusion per the Lugano classification for Phase I and Cohort 6b, and per iwCLL criteria for Richter Transformation of Diffuse Large B-cell Lymphoma (DLBCL-RT, Cohort 7).

Further secondary endpoints encompass the evaluation of Complete Response (CR) until two years post-infusion, Duration of Response (DOR), Duration of Complete Response (DOCR), Progression-Free Survival (PFS), and Overall Survival (OS). The trial will also assess Minimal Residual Disease (MRD) negativity rate at CR for DLBCL, Mantle Cell Lymphoma (MCL), and DLBCL-RT. Biomarker analysis will include levels of anti-CD19 CAR T cells in blood at peak and over time, as well as levels of chemokines and cytokines in serum over time. The proportion of successfully manufactured products within predefined release specifications will be monitored. Additionally, changes from baseline in Health-Related Quality of Life (HRQoL) will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and its CLL-specific module QLQCLL-17 for DLBCL-RT, and the EuroQol EQ-5D-5L.