Evaluation of Epcoritamab in Combination with Chemotherapeutic Agents in B-cell Non-Hodgkin Lymphoma: A Phase 1b/2 Open-Label Study

The primary objective of this Phase 1b/2 open-label trial is to evaluate the **safety** and tolerability of epcoritamab in combination with other agents in subjects with B-cell non-Hodgkin lymphoma. This is clinically relevant as it aims to determine the potential of epcoritamab to be safely integrated into existing treatment regimens, potentially enhancing therapeutic outcomes for patients with this type of lymphoma.

Secondary objectives include:

• Characterizing the pharmacokinetic properties of epcoritamab.
• Evaluating pharmacodynamic markers linked to the efficacy and mechanism of action of epcoritamab.
• Assessing immunogenicity.
• Assessing the preliminary anti-tumor activity of epcoritamab in combination with other agents during the dose escalation phase.
• Further assessing the preliminary anti-tumor activity of epcoritamab as a component of a treatment regimen during the expansion phase.
• Further evaluating the safety and tolerability of epcoritamab in combination with other agents during the expansion phase.

The clinical trial involves a total of **188 participants** diagnosed with **lymphoma of B-cell origin**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who are part of a vulnerable population. Participants were selected based on specific inclusion criteria, such as having measurable disease, an ECOG performance status score of 0, 1, or 2, and acceptable organ function at screening. The trial also considers lifestyle factors, requiring participants of childbearing potential to practice a highly effective method of birth control. The study does not specify any particular dietary or physical activity requirements. The selection process ensures that participants have a life expectancy of more than two months with standard of care treatment, and they must have a confirmed diagnosis of CD20-positive non-Hodgkin lymphoma at the most recent tumor biopsy. The trial aims to evaluate the safety, tolerability, and preliminary anti-tumor activity of epcoritamab in combination with other agents.

The clinical trial is designed to evaluate the safety and preliminary efficacy of **epcoritamab** in combination with other agents in subjects with B-cell non-Hodgkin lymphoma. This trial is structured as a Phase 1b/2, open-label study, with a dose escalation phase followed by an expansion phase. The trial is expected to run from July 2020 to July 2028, with participant involvement varying based on the specific arm of the study they are enrolled in.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, measurable disease, and organ function. Following successful screening, participants will enter the dose escalation phase, where the primary endpoints include the incidence of dose-limiting toxicities and adverse events. The expansion phase will focus on assessing the preliminary anti-tumor activity of the drug combinations. Study visits will include regular monitoring of safety parameters, laboratory values, and the occurrence of adverse events.

The trial includes multiple arms, each with specific objectives and endpoints. For instance, Arms 1-6 and 8-10 will assess the overall response rate (ORR) using the Lugano criteria, while Arm 7 will focus on the safety and tolerability of **epcoritamab** following standard care. Participants are expected to remain in the study until the end-of-study visit unless they meet conditions for early termination, such as significant adverse events or withdrawal of consent.

Participant involvement is anticipated to last until the study's completion or until they meet criteria for discontinuation. Conditions for early termination include the development of unacceptable toxicity, non-compliance with study procedures, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to evaluate the safety and efficacy of the investigational drug combinations in treating B-cell non-Hodgkin lymphoma.

The clinical trial involves the administration of several experimental and non-experimental treatments to assess their safety and efficacy in subjects with B-cell Non-Hodgkin Lymphoma. **Epcoritamab**, a biological/biotechnological agent, is administered as a **solution for injection** via the **subcutaneous** route. It is a monoclonal antibody targeting CD3 and CD20, with the sponsor product code GEN3013. Epcoritamab is used in combination with other agents to evaluate its safety and preliminary anti-tumor activity.

**Carboplatin** is a chemical antineoplastic agent administered **intravenously**. It is used in its pharmaceutical form PHF00230MIG. The administration schedule and dosage are determined based on the trial protocol, and participant compliance is monitored throughout the study.

**Rituximab**, a biological monoclonal antibody, is also administered **intravenously** in the form PHF00230MIG. It is used in combination with other agents to enhance the therapeutic effect against B-cell Non-Hodgkin Lymphoma.

**Gemcitabine Hydrochloride** is another chemical antineoplastic agent administered **intravenously**. It is provided in the pharmaceutical form PHF00230MIG, and its administration is carefully monitored to ensure participant safety and compliance.

**Tocilizumab**, a biological agent, is administered **intravenously** in the form PHF00231MIG. It is used to modulate immune responses and is part of the combination therapy in the trial.

**Lenalidomide** is administered **orally** in the form PHF00006MIG. It is a chemical agent used as part of the standard-of-care therapy in the trial.

**Cytarabine** is a chemical antineoplastic agent administered **intravenously** in the form PHF00230MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Prednisolone** is administered **intravenously** in the form PHF00245MIG. It is a chemical agent used to manage inflammation and immune responses in the trial.

**Vinorelbine** is administered **intravenously** in the form PHF00007MIG. It is a chemical agent used as part of the combination therapy in the trial.

**Anakinra**, a biological/biotechnological agent, is administered **subcutaneously** in the form PHF00231MIG. It is used to modulate immune responses in the trial.

**Dexamethasone Isonicotinate** is administered **intravenously** in the form PHF00024MIG. It is a chemical agent used to manage inflammation and immune responses in the trial.

**Ifosfamide** is a chemical antineoplastic agent administered **intravenously** in the form PHF00230MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Siltuximab**, a biological agent, is administered **intravenously** in the form PHF00230MIG. It is used to modulate immune responses and is part of the combination therapy in the trial.

**Oxaliplatin** is a chemical agent administered **intravenously** in the form PHF00230MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Diphenhydramine** is administered **intravenously** in the form PHF00245MIG. It is a chemical agent used to manage allergic reactions and is part of the standard-of-care therapy in the trial.

**Etoposide** is a chemical antineoplastic agent administered **intravenously** in the form PHF675. It is used in combination with other agents to enhance the therapeutic effect.

**Cyclophosphamide** is a chemical agent administered **intravenously** in the form PHF00231MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Bendamustine Hydrochloride** is a chemical agent administered **intravenously** in the form PHF00230MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Betamethasone Sodium Phosphate** is administered **orally** in the form PHF00059MIG. It is a chemical agent used to manage inflammation and immune responses in the trial.

**Doxorubicin Hydrochloride** is a chemical agent administered **intravenously** in the form PHF00231MIG. It is used in combination with other agents to enhance the therapeutic effect.

**Buclizine Hydrochloride, Paracetamol, Codeine Phosphate** is administered **orally** in the form PHF00082MIG. It is a chemical combination used to manage symptoms and is part of the standard-of-care therapy in the trial.

The clinical trial aims to assess the efficacy of **Epcoritamab** in combination with other agents in subjects with B-cell Non-Hodgkin Lymphoma. Efficacy will be evaluated through several primary and secondary endpoints. In the Dose Escalation Phase, primary endpoints include the incidence of dose-limiting toxicities, adverse events (AEs), changes in laboratory values, and dose interruptions and delays. In the Expansion Phase, the primary endpoint for Arms 1-6 and 8-10 is the Overall Response Rate (ORR) determined by the Lugano criteria, while Arm 7 focuses on the incidence and severity of AEs, changes in laboratory values, and dose interruptions and delays.

Secondary endpoints in the Dose Escalation Phase include pharmacokinetic (PK) parameters, pharmacodynamic markers in blood samples and within tumors, incidence of anti-drug antibodies (ADAs) to Epcoritamab, ORR, duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), time to next treatment (TTNT), and rate and duration of minimal residual disease (MRD) negativity. In the Expansion Phase, secondary endpoints include DOR, TTR, PFS, complete response (CR) rate, OS, TTNT, rate and duration of MRD negativity, rate of conversion from MRD positivity to MRD negativity, CR rate for Arm 7 subjects in partial response (PR) at baseline, time to complete response (TTCR), and duration of complete response (DoCR).