A Phase 3, Open-Label, Randomized Study To Compare the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20 x Anti-CD3 Bispecific Antibody, Combined with Chemotherapy versus Rituximab Combined with Chemotherapy in Previously Untreated Participants with Follicular Lymphoma (OLYMPIA-2)

The primary objective of this study is to assess the **safety**, tolerability, and dose-limiting toxicities (DLTs) of odronextamab in combination with chemotherapy in participants with previously untreated follicular lymphoma (FL) and those with relapsed or refractory FL (Part 1A only). Additionally, the study aims to determine an optimal dosing regimen of odronextamab (Part 1B) in previously untreated participants with FL to combine with CHOP/CVP in Part 2. This is clinically relevant as it seeks to establish a safe and effective treatment protocol for patients with FL, potentially improving therapeutic outcomes.

Secondary objectives include:

• Characterizing the pharmacokinetics (PK) and assessing the immunogenicity of odronextamab in combination with chemotherapy.
• Evaluating the preliminary anti-tumor activity of odronextamab in combination with chemotherapy.
• Comparing the efficacy of odronextamab in combination with chemotherapy versus rituximab in combination with chemotherapy, as measured by progression-free survival (PFS) and complete response rate at 30 months (CR30) per independent central review.
• Assessing changes over time in patient-reported physical functioning and other outcomes, including health-related quality of life (HRQoL) and symptoms.
• Evaluating the overall impact of treatment toxicity using the Global Population item 5 (GP5 Item) of the validated FACT-G questionnaire.

The clinical trial involves a total of **513 participants** diagnosed with **follicular lymphoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a diagnosis of cluster of differentiation 20 positive (CD20+) follicular lymphoma grade 1-3a, stage II bulky or stage III/IV, and the presence of measurable disease as confirmed by cross-sectional imaging techniques such as CT or MRI. The general health status of participants is assessed through the Eastern Cooperative Oncology Group (ECOG) performance status, with eligible individuals having a status of 0-2, indicating they are fully active or capable of self-care. Additionally, participants are required to have adequate bone marrow and hepatic function. The trial does not include vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy and safety of **odronextamab** combined with chemotherapy compared to **rituximab** combined with chemotherapy in participants with previously untreated **follicular lymphoma**. The trial is structured into two parts, with Part 1 focusing on assessing the safety, tolerability, and dose-limiting toxicities of odronextamab in combination with chemotherapy, and Part 2 comparing the efficacy of the two treatment regimens. The primary endpoint for Part 2 is the complete response rate at 30 months, assessed by independent central review.

The trial is expected to last until October 2029, with participant involvement potentially extending up to 856 days, depending on the treatment regimen. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a diagnosis of CD20+ follicular lymphoma, measurable disease, and adequate bone marrow and hepatic function. Following the screening, participants will be randomized to receive either odronextamab or rituximab in combination with chemotherapy. Regular follow-up visits will be conducted to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for the participant's safety. The study will also monitor secondary endpoints, including odronextamab concentrations, incidence of anti-drug antibodies, progression-free survival, and changes in patient-reported outcomes. The trial's design ensures rigorous assessment of both safety and efficacy, providing valuable data on the potential benefits of odronextamab in treating follicular lymphoma.

The clinical trial involves the administration of **Odronextamab**, a concentrate for solution for infusion, which is an experimental medication. Odronextamab is a bispecific monoclonal antibody targeting CD20 and CD3, and is administered via **intravenous infusion**. The maximum daily dose is 320 mg, with a total treatment period of up to 856 days. This medication is provided by Regeneron Pharmaceuticals, Inc. and is designated as an orphan drug for this study.

**Truxima**, containing the active substance **Rituximab**, is used as a comparator treatment. It is available in two formulations: 500 mg and 100 mg concentrates for solution for infusion. Both formulations are administered **intravenously** with a maximum daily dose of 375 mg/m². The treatment period can extend up to 856 days. Truxima is manufactured by Celltrion Healthcare Hungary Kft.

**Prednisone** is included as part of the chemotherapy regimen. It is administered orally in tablet form, with a maximum daily dose of 100 mg. The treatment duration is limited to 126 days. Prednisone serves as a standard-of-care therapy in combination with other chemotherapeutic agents.

**Doxorubicin Hydrochloride** is another component of the chemotherapy regimen, provided as a solution for injection. It is administered **intravenously** with a maximum daily dose of 50 mg/m², over a treatment period of 126 days. This chemotherapeutic agent is used in conjunction with other medications to enhance treatment efficacy.

**Cyclophosphamide** is administered as a solution for injection or infusion, with a maximum daily dose of 750 mg/m². The administration route is **intravenous**, and the treatment period is 126 days. Cyclophosphamide is a standard chemotherapeutic agent used in combination with other drugs in this trial.

**Vincristine Sulfate** is provided as an injection, administered with a maximum daily dose of 1.4 mg/m². The administration is via **injection**, and the treatment duration is 126 days. Vincristine Sulfate is part of the chemotherapy regimen used in this study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to assess the efficacy and safety of Odronextamab in combination with chemotherapy compared to Rituximab combined with chemotherapy in participants with previously untreated follicular lymphoma.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Part 2 of the study is the **Complete Response rate at 30 months (CR30)**, which will be evaluated by an independent central review. This endpoint is crucial for determining the effectiveness of **odronextamab** in combination with chemotherapy compared to **rituximab** combined with chemotherapy in participants with previously untreated **follicular lymphoma**.

Secondary endpoints include various measures such as **Progression Free Survival (PFS)**, **Event-Free Survival (EFS)**, and **Overall Survival (OS)**, all assessed by independent central review and local investigators. Additionally, the study will evaluate the incidence and titers of anti-odronextamab antibodies (ADAs), the incidence of neutralizing antibodies (NAb) to odronextamab, and changes in patient-reported outcomes using validated instruments like the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (EORTC-QLQ-C30) and the Functional Assessment of Cancer Treatment-Lymphoma (FACT-LymS).

Data collection will occur at specified intervals throughout the trial, with assessments conducted by both independent central review and local investigators to ensure comprehensive evaluation. The use of validated scales and patient-reported outcomes will provide a robust framework for assessing the efficacy of the treatment regimens under investigation.