Phase 3 Randomized Open-Label Trial of Epcoritamab Versus Investigator's Choice Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma

The primary objective of this Phase 3 trial is to compare the **clinical efficacy** of **epcoritamab** to the standard of care (SOC), specifically R-GemOx or BR, in patients with relapsed/refractory diffuse large B-cell lymphoma. This comparison is clinically relevant as it aims to establish whether epcoritamab offers superior therapeutic benefits over existing treatment options, potentially leading to improved patient outcomes in this challenging condition.

Secondary objectives include:

• Comparing other measures of epcoritamab efficacy to SOC.
• Comparing the safety and tolerability of epcoritamab to SOC.
• Evaluating the **immunogenicity** of epcoritamab.
• Comparing patient-reported outcomes (PROs) related to lymphoma symptoms between epcoritamab and SOC.

The clinical trial involves a total of **303 participants** diagnosed with **B-cell Lymphoma**, specifically targeting subtypes such as DLBCL, NOS, "double-hit" or "triple-hit" DLBCL, FL Grade 3B, and T-cell/histiocyte-rich large B-cell lymphoma. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. Participants were selected based on their relapsed or refractory disease status, having been previously treated with at least one line of systemic antineoplastic therapy, including anti-CD20 monoclonal antibody-containing combination chemotherapy. The trial population includes individuals with measurable disease, as confirmed by imaging techniques such as FDG-PET scans, CT, or MRI. Key lifestyle considerations include the requirement for female participants to agree not to donate eggs and to use adequate contraception during and after the trial, while male participants must agree to use a barrier method of birth control and not donate sperm. The trial also includes a vulnerable population, ensuring comprehensive representation of the affected demographic. Participants must have a life expectancy of more than two months on standard of care treatment. The selection criteria ensure that the study population is representative of the clinical condition under investigation, providing a robust basis for evaluating the efficacy of epcoritamab compared to standard care treatments.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study comparing the efficacy of **epcoritamab** against investigator's choice chemotherapy in patients with relapsed or refractory **B-cell lymphoma**. The trial aims to evaluate the clinical efficacy of epcoritamab in comparison to standard of care treatments, specifically R-GemOx or BR regimens. The study is expected to run from September 1, 2020, to April 14, 2029, with an estimated participant involvement duration of up to 108 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, ECOG performance status, and previous treatment history. Following successful screening, participants will be randomized to receive either epcoritamab or the investigator's choice chemotherapy. The trial includes regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will involve assessments such as imaging studies, laboratory tests, and physical examinations.

The primary endpoints of the trial are overall survival and progression-free survival, as determined by the Lugano criteria through independent review committee assessment. Secondary endpoints include progression-free survival by investigator assessment, overall response rate, complete response rate, duration of response, and time to response, among others. The trial will also evaluate the incidence and severity of adverse events, changes in laboratory values, and the development of anti-epcoritamab antibodies.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, any significant protocol deviations or non-compliance with study procedures may lead to early termination from the trial. The study is not categorized as low intervention, given the investigational nature of the drug in the population involved.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Epcoritamab** is the primary investigational drug, administered as a **solution for injection**. It is a protein-based monoclonal antibody targeting CD3E and MS4A1, with a maximum daily dose of 48 mg and a total dose of 5616.96 mg over a treatment period of 108 weeks. The route of administration is **subcutaneous**.

**Dexamethasone isonicotinate** is used as a comparator treatment. It is administered orally with a maximum daily dose of 15 mg and a total dose of 240 mg over 16 days. The pharmaceutical form is coded as PHF00024MIG.

Another comparator, **Paracetamol**, combined with **Buclizine hydrochloride** and **Codeine phosphate**, is administered orally. The maximum daily dose is 1000 mg, with a total dose of 4000 mg over 4 days. The pharmaceutical form is PHF00082MIG.

**Oxaliplatin** is administered intravenously as a comparator, with a maximum daily dose of 100 mg/m² and a total dose of 800 mg/m² over 112 days. The pharmaceutical form is PHF00230MIG.

**Gemcitabine hydrochloride** is also administered intravenously as a comparator, with a maximum daily dose of 1000 mg/m² and a total dose of 8000 mg/m² over 112 days. The pharmaceutical form is PHF00230MIG.

**Tocilizumab** is used as an auxiliary treatment, administered intravenously with a maximum daily dose of 1600 mg over a single day. The pharmaceutical form is PHF00231MIG.

**Rituximab** is administered intravenously as a comparator, with a maximum daily dose of 375 mg/m² and a total dose of 3000 mg/m² over 112 days. The pharmaceutical form is PHF00230MIG.

**Anakinra** is used as an auxiliary treatment, administered subcutaneously with a maximum daily dose of 200 mg and a total dose of 400 mg over 10 days. The pharmaceutical form is PHF00231MIG.

**Siltuximab** is administered intravenously as an auxiliary treatment, with a maximum daily dose of 11 mg/kg over a single day. The pharmaceutical form is PHF00230MIG.

**Bendamustine hydrochloride** is administered intravenously as a comparator, with a maximum daily dose of 90 mg/m² and a total dose of 1080 mg/m² over 126 days. The pharmaceutical form is PHF00230MIG.

**Diphenhydramine** is used as an auxiliary treatment, administered orally with a maximum daily dose of 50 mg and a total dose of 200 mg over 4 days. The pharmaceutical form is PHF00245MIG.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to compare the clinical efficacy of **Epcoritamab** against standard-of-care therapies, including R-GemOx or BR, in patients with relapsed/refractory diffuse large B-cell lymphoma.

The clinical trial aims to assess the efficacy of **Epcoritamab** compared to standard of care (SOC) chemotherapy regimens, specifically R-GemOx or BR, in patients with relapsed/refractory diffuse large B-cell lymphoma. The primary efficacy endpoints include overall survival (OS) and progression-free survival (PFS) as determined by the Lugano criteria, assessed by an independent review committee (IRC). Secondary efficacy endpoints encompass a range of measures, including PFS by investigator assessment, overall response rate (ORR), complete response (CR) rate, duration of response (DOR), and time to response (TTR), all evaluated using the Lugano criteria by both IRC and investigator assessments. Additional secondary endpoints include the rate and duration of minimal residual disease (MRD) negative status, PFS determined by Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC), and ORR, CR rate, DOR, and TTR as per LYRIC criteria by IRC assessment. The trial will also measure time to next anti-lymphoma therapy (TTNT), incidence and severity of adverse events (AEs), changes in laboratory values, incidence of dose interruptions and delays, anti-epcoritamab antibody response, and changes in lymphoma symptoms using the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym).