A Phase 3, Randomized, Open Label Study Evaluating the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20 x Anti-CD3 Bispecific Antibody, versus Standard of Care Therapy in Participants with Relapsed/Refractory Aggressive B-cell non-Hodgkin Lymphoma (OLYMPIA-4)

The primary objective of this study is to compare the **efficacy** of odronextamab, an anti-CD20 x anti-CD3 bispecific antibody, with standard of care (SOC) therapy in participants with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Efficacy is defined by event-free survival (EFS), a critical endpoint in assessing the potential of odronextamab to improve patient outcomes in this challenging clinical setting.

Secondary objectives include:

• Comparing additional measures of efficacy for odronextamab versus SOC therapy.
• Comparing the treatment effects on patient-reported physical function between odronextamab monotherapy and SOC.
• Comparing safety and tolerability of odronextamab monotherapy versus SOC.
• Assessing the pharmacokinetics (PK) and immunogenicity of odronextamab monotherapy.
• Comparing measurable residual disease (MRD) of odronextamab monotherapy versus SOC.
• Comparing the effect of odronextamab monotherapy versus SOC on patient-reported outcomes, including Health-Related Quality of Life (HRQoL), symptoms, and functioning.
• Evaluating the patient-reported overall impact of treatment toxicity of odronextamab monotherapy versus SOC.

The clinical trial involves a total of **124 participants** diagnosed with **B-Cell Non-Hodgkin's Lymphoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically proven aggressive form of B-NHL, primary refractory or relapse within 12 months from the initiation of frontline therapy, and measurable disease as documented by diagnostic imaging. All participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include vulnerable populations, and all participants must have adequate hematologic and organ function. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to compare the efficacy of odronextamab versus Standard of Care (SOC) in terms of event-free survival (EFS).

The clinical trial is a **randomized**, open-label study designed to evaluate the efficacy and safety of **odronextamab**, an anti-CD20 x anti-CD3 bispecific antibody, compared to standard of care therapy in participants with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. The primary objective is to compare event-free survival (EFS) between the two treatment groups. Secondary endpoints include progression-free survival, best overall response, and overall survival, among others. The trial is expected to last until May 2027, with recruitment starting in June 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically proven aggressive B-cell non-Hodgkin's lymphoma, measurable disease, and adequate organ function. Following randomization, participants will receive either odronextamab or standard chemotherapy regimens, including agents such as **gemcitabine**, **dexamethasone**, and **carboplatin**. Treatment will continue for a maximum of 12 months for odronextamab and 9 months for chemotherapy, depending on the specific regimen.

Study visits will include regular assessments to monitor treatment response and safety, with evaluations conducted by independent central review and local investigators. Participants will be required to attend follow-up visits at specified intervals to assess primary and secondary endpoints. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the treatment of aggressive B-cell non-Hodgkin's lymphoma.

The clinical trial involves the administration of **Odronextamab**, a **concentrate for solution for infusion**. This experimental medication is a bispecific monoclonal antibody targeting CD20 and CD3, known by the sponsor product code REGN1979. It is administered intravenously with a maximum daily dose of 320 mg, and the treatment period extends up to 12 months. Odronextamab is developed by Regeneron Pharmaceuticals, Inc., and is designated as an orphan drug for this study.

**Gemcitabine** is utilized as a comparator treatment in the study. It is provided as a **solution for infusion** and is administered intravenously. The maximum daily dose is 1 gm/m², with a treatment period of up to 9 months. Gemcitabine is a chemical substance used in chemotherapy protocols.

**Dexamethasone** is included in the study as a non-experimental treatment. It is available in both **tablet** and **solution for injection** forms. The oral administration involves a maximum daily dose of 40 mg, while the injectable form is administered intravenously with the same dosage limit. The treatment duration is up to 9 months.

**Carboplatin** is another comparator treatment, provided as a **solution for infusion**. It is administered intravenously with a maximum daily dose of 800 mg/m², and the treatment period is up to 9 months. Carboplatin is a chemical substance used in chemotherapy.

**Ifosfamide** is administered as a **solution for injection/infusion**. It is given intravenously with a maximum daily dose of 5 gm/m², and the treatment period is up to 9 months. Ifosfamide is a chemical substance used in chemotherapy protocols.

**Cytarabine** is included as a **solution for injection**. It is administered intravenously with a maximum daily dose of 4 gm/m², and the treatment period is up to 9 months. Cytarabine is a chemical substance used in chemotherapy.

**Cisplatin** is provided as a **solution for infusion** and is administered intravenously. The maximum daily dose is 100 mg/m², with a treatment period of up to 9 months. Cisplatin is a chemical substance used in chemotherapy.

**Etoposide** is administered as a **solution for infusion**. It is given intravenously with a maximum daily dose of 100 mg/m², and the treatment period is up to 9 months. Etoposide is a chemical substance used in chemotherapy.

**Rituximab** is included as a **solution for infusion**. It is administered intravenously with a maximum daily dose of 375 mg/m², and the treatment period is up to 9 months. Rituximab is a chemical substance used in chemotherapy.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy and safety of Odronextamab compared to standard-of-care therapies in participants with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

The efficacy of the clinical trial will be assessed primarily through **event-free survival (EFS)**, as evaluated by an independent central review. Secondary endpoints include **progression-free survival (PFS)**, **best overall response (BOR)**, and **complete response (CR)**, all assessed by both independent central review and local investigators. Additional secondary endpoints involve the overall change in physical functioning, measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30), and overall survival (OS).

Other efficacy parameters include the duration of response (DOR), incidence and severity of treatment-emergent adverse events (TEAEs), and measurable residual disease (MRD) status. The study will also evaluate odronextamab concentrations in serum, incidence and titers of anti-drug antibodies (ADAs), and neutralizing antibodies (NAb) to odronextamab over the study duration. Patient-reported outcomes will be measured using the EORTC-QLQ-C30, Functional Assessment of Cancer Therapy–Lymphoma (FACT-LymS), EuroQol-5 Dimension-5 Level Scale (EQ-5D-5L), and the Global Population item 5 (GP5) of the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire.