Phase 3 Randomized Study of Epcoritamab Plus R-CHOP Versus R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients

The primary objective of this study is to evaluate whether the addition of **epcoritamab** to 6 cycles of standard R-CHOP followed by 2 cycles of epcoritamab can prolong **progression-free survival (PFS)** compared with 6 cycles of standard R-CHOP alone followed by 2 cycles of rituximab in subjects with newly diagnosed **Diffuse Large B-Cell Lymphoma (DLBCL)** with an **International Prognostic Index (IPI)** of 3-5. This is clinically relevant as improving PFS can potentially lead to better long-term outcomes and quality of life for patients with DLBCL.

Secondary objectives include: - Evaluating and comparing PFS between the two treatment arms in subjects with newly diagnosed DLBCL with an IPI of 2-5, encompassing all randomized subjects. - Evaluating and comparing each key secondary endpoint for both the subset of subjects with an IPI of 3-5 and all randomized subjects, following the hierarchical order specified in the study protocol.

The clinical trial involves a total of **475 participants** diagnosed with **Diffuse Large B-Cell Lymphoma (DLBCL)**. The study population includes both male and female subjects, aged between 18 and 79 years, with a life expectancy of at least 12 months. Participants were selected based on their planned treatment with 6 cycles of standard R-CHOP, as determined by the investigator, and must have an International Prognostic Index (IPI) score of 2-5, with the number of subjects having an IPI score of 2 not exceeding approximately 30% of the overall sample size. The trial does not include vulnerable populations. The selection criteria ensure that participants are in a general health status suitable for the study's requirements, although specific lifestyle considerations such as diet or physical activity are not detailed in the provided data.

The clinical trial is a **randomized**, open-label study designed to evaluate the safety and efficacy of **epcoritamab** in combination with R-CHOP compared to R-CHOP alone in subjects with newly diagnosed **Diffuse Large B-Cell Lymphoma (DLBCL)**. The trial aims to determine whether the addition of epcoritamab can prolong progression-free survival (PFS) compared to the standard R-CHOP regimen. The study is expected to run until August 2029, with recruitment having commenced in February 2023.

Participants will be involved in the study for a maximum treatment period of 24 months. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The primary endpoint is PFS, defined as the duration from randomization to disease progression or death from any cause, assessed by an independent review committee using the Lugano criteria. Secondary endpoints include overall survival (OS), complete response (CR) rates, and minimal residual disease (MRD) negativity.

Inclusion criteria require participants to be between 18 and 80 years old, with a life expectancy of at least 12 months, and an International Prognostic Index (IPI) score of 2-5. Participants must be planned to receive 6 cycles of standard R-CHOP. The study will exclude individuals who do not meet these criteria. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other reason deemed necessary by the investigator.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Epcoritamab (GEN3013)** is the experimental medication in this study. It is a bispecific antibody provided as a **solution for injection**. The administration route is **subcutaneous injection**. The dosing schedule includes 6 cycles of standard R-CHOP followed by 2 cycles of Epcoritamab. The maximum treatment period is 24 months. Epcoritamab is not a pediatric formulation and is designated as an orphan drug.

**Truxima**, containing the active substance **rituximab**, is used as a comparator in the study. It is available in two formulations: 500 mg and 100 mg concentrates for solution for infusion. The pharmaceutical form is a **solution for infusion**, administered via **intravenous infusion**. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of 24 months. Truxima is not a pediatric formulation.

**Vincristine Sulfate** is another comparator used in the trial. It is provided as a **solution for injection** and administered through **intravenous infusion**. The maximum daily dose is 2 mg/mL, with a total maximum dose of 12 mg/mL over an 18-month treatment period. This medication is not formulated for pediatric use.

**Doxorubicin Hydrochloride**, marketed as Doxorubicinhydrochlorid Bendalis, is also included as a comparator. It is available as a **solution for injection** and administered via **intravenous infusion**. The maximum daily dose is 50 mg/m², with a total maximum dose of 300 mg/m² over an 18-month treatment period. This formulation is not intended for pediatric use.

**Cyclophosphamide** is administered as a **solution for injection** through **intravenous infusion**. The maximum daily dose is 750 mg/m², with a total maximum dose of 4500 mg/m² over an 18-month treatment period. This medication is not a pediatric formulation.

**Prednisone**, marketed as Prednisone Zentiva, is provided in **tablet** form and administered **orally**. The maximum daily dose is 100 mg, with a total maximum dose of 3000 mg over an 18-month treatment period. This formulation is not intended for pediatric use.

Participant compliance with the dosing schedule and administration routes will be monitored throughout the trial to ensure adherence to the protocol. The study aims to evaluate the safety and efficacy of Epcoritamab in combination with R-CHOP compared to R-CHOP alone in subjects with newly diagnosed Diffuse Large B-Cell Lymphoma (DLBCL).

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. PFS is defined as the duration from the date of randomization to the date of either death due to any cause or disease progression, as determined by an independent review committee (IRC) using the Lugano criteria. The primary analysis will focus on subjects with an International Prognostic Index (IPI) score of 3-5. Secondary endpoints include PFS in all randomized subjects, complete response (CR) on or after the end of treatment (EOT) based on IRC assessment per Lugano criteria, overall survival (OS) defined as the time from randomization until death due to any cause, and minimal residual disease (MRD) negativity.