Phase 1/2 Open-Label Dose-Escalation Study of Epcoritamab in Relapsed, Progressive, or Refractory B-Cell Lymphoma with Anakinra and Drug Combination

The primary objective of this Phase 1/2, open-label, dose-escalation trial is to determine the **maximum tolerated dose** and the recommended Phase 2 dose of **epcoritamab** in patients with relapsed, progressive, or refractory B-cell lymphoma. This is clinically relevant as it aims to establish a safe and effective dosing regimen for further clinical evaluation, potentially improving therapeutic outcomes for patients with this challenging condition.

Secondary objectives include:

• Escalation Phase: Establish the tolerability of epcoritamab, determine its pharmacokinetic (PK) profile after single and multiple doses, evaluate immunogenicity, and assess anti-lymphoma activity.
• Expansion and Optimization Part: Further evaluate clinical efficacy using the Lugano criteria and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC), assess minimal residual disease (MRD) status as a clinical efficacy endpoint, evaluate safety and tolerability, and assess patient-reported outcomes related to lymphoma symptoms. Additionally, evaluate the PK and immunogenicity of epcoritamab and the safety and tolerability of alternative priming/intermediate dosing regimens.

The clinical trial involves a total of **312 participants** diagnosed with **Lymphoma of B-cell origin**. The study population includes both male and female subjects, aged 18 years and older, with specific age considerations in countries where the legal age is 21. Participants are required to have a documented CD20+ mature non-Hodgkin B-cell lymphoma, with relapsed, progressive, and/or refractory disease following treatment with an anti-CD20 monoclonal antibody. All participants must have received at least two prior lines of therapy and have measurable disease by imaging. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with specific requirements for Mantle Cell Lymphoma (MCL) participants. The selection process ensures the inclusion of a vulnerable population, adhering to ethical standards. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase 1/2, open-label, dose-escalation study** to evaluate the safety and efficacy of **epcoritamab** in patients with relapsed, progressive, or refractory B-cell lymphoma. The trial aims to determine the maximum tolerated dose and recommended phase 2 dose during the escalation phase, assess clinical efficacy using the Lugano criteria in the expansion phase, and explore alternative dosing regimens to reduce the risk of cytokine release syndrome (CRS) in the optimization part. The study is expected to run from February 28, 2018, to February 28, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented CD20+ mature non-Hodgkin B-cell lymphoma, and previous treatment history. Follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetics, with assessments including dose-limiting toxicity, adverse events, and overall response rate. The end-of-study visit will conclude the participant's involvement, which is anticipated to last until the study's completion or until early termination criteria are met.

Early termination from the study may occur if participants experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial will employ a rigorous methodology, including independent review committee assessments and adherence to the Lugano criteria for evaluating response rates. The study will not involve any pediatric formulations, and all investigational products will be administered via subcutaneous or intravenous routes as appropriate.

The clinical trial involves the administration of **Epcoritamab**, a solution for injection, which is the primary experimental medication. Epcoritamab is a monoclonal antibody targeting CD3 and MS4A1, also known as DuoBody-CD3xCD20. It is administered via **subcutaneous use**. The trial aims to determine the maximum tolerated dose and evaluate clinical efficacy in patients with relapsed, progressive, or refractory B-cell lymphoma. Epcoritamab is provided by GENMAB and is designated as an orphan drug with the code GEN3013.

**Anakinra** is used as an auxiliary treatment in the trial. It is a protein-based medication administered through **subcutaneous use**. Anakinra is utilized to manage inflammatory responses and is not a pediatric formulation. The pharmaceutical form is coded as PHF00231MIG.

**Diphenhydramine** is included as an auxiliary treatment, administered orally. It is a chemical substance used to manage allergic reactions and is not a pediatric formulation. The pharmaceutical form is coded as PHF00245MIG.

**Betamethasone Sodium Phosphate** is another auxiliary treatment, administered via **intravenous administration**. It is a chemical substance used for its anti-inflammatory properties. The pharmaceutical form is coded as PHF00059MIG, and it is not a pediatric formulation.

**Paracetamol**, combined with **Buclizine Hydrochloride** and **Codeine Phosphate**, is administered orally as an auxiliary treatment. This combination is used for pain relief and is not a pediatric formulation. The pharmaceutical form is coded as PHF00082MIG.

**Dexamethasone Acetate** is administered intravenously as an auxiliary treatment. It is a chemical substance used for its anti-inflammatory and immunosuppressant effects. The pharmaceutical form is coded as PHF00245MIG, and it is not a pediatric formulation.

**Tocilizumab** is used as an auxiliary treatment, administered via **intravenous use**. It is a protein-based medication used to manage inflammatory responses. The pharmaceutical form is coded as PHF00231MIG, and it is not a pediatric formulation.

**Siltuximab** is included as an auxiliary treatment, administered via **intravenous use**. It is a chimeric monoclonal antibody targeting interleukin-6, used to manage inflammatory conditions. The pharmaceutical form is coded as PHF00230MIG, and it is not a pediatric formulation.

The clinical trial aims to assess the efficacy of **Epcoritamab** in patients with relapsed, progressive, or refractory B-cell lymphoma. Efficacy will be evaluated using several endpoints, primarily determined by the Lugano criteria. The primary efficacy endpoint in the expansion phase is the overall response rate (ORR) as assessed by an independent review committee (IRC). Secondary efficacy endpoints include duration of response (DOR), complete response (CR) rate, duration of CR (DoCR), progression-free survival (PFS), and time to response (TTR), all determined by the Lugano criteria. Additionally, the trial will assess objective and best response rates, PFS, DOR, DoCR, and TTR using the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). Overall survival (OS) and time to next anti-lymphoma therapy (TTNT) will also be evaluated.

Patient-reported outcomes will be measured using the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) to assess changes in lymphoma symptoms. Safety parameters, including adverse events, laboratory parameters, hospitalizations, and cytokine measures, will be monitored. Pharmacokinetic (PK) parameters such as clearance, volume of distribution, maximum concentration (Cmax), time of Cmax (Tmax), trough concentrations, and half-life will be analyzed. The incidence of anti-drug antibodies (ADAs) to GEN3013 will also be assessed. The trial will monitor the rate of ≥ Grade 2 cytokine release syndrome (CRS) events and all-grade CRS events following the first full dose and overall. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's efficacy and safety.