A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY TO COMPARE THE EFFICACY AND SAFETY OF ODRONEXTAMAB (REGN1979), AN ANTI-CD20 X ANTI-CD3 BISPECIFIC ANTIBODY, VERSUS INVESTIGATOR’S CHOICE IN PREVIOUSLY UNTREATED PARTICIPANTS WITH FOLLICULAR LYMPHOMA (OLYMPIA-1)

The primary objective of this study is to assess the **safety**, tolerability, and dose-limiting toxicities (DLTs) of odronextamab in participants with previously untreated **follicular lymphoma** during Part 1 (Safety Run-in). In Part 2 (Randomized Phase), the study aims to compare the efficacy of odronextamab versus investigator’s choice chemotherapy in participants with previously untreated follicular lymphoma, as measured by complete response at 30 months (CR30) per independent central review. This is clinically relevant as it evaluates the potential of odronextamab as a first-line treatment option, which could improve patient outcomes in follicular lymphoma.

Secondary objectives include:

• Part 1: Characterizing the pharmacokinetics (PK) of odronextamab, assessing its immunogenicity, and evaluating its preliminary anti-tumor activity.
• Part 2: Comparing the efficacy per independent central review between odronextamab monotherapy and investigator’s choice chemotherapy, as measured by progression-free survival (PFS) and event-free survival (EFS). Additionally, the study will compare efficacy as measured by CR30 per investigator, evaluate treatment effects on patient-reported physical function using the EORTC-QLQ-C30, and assess additional measures of efficacy. Safety and tolerability of odronextamab compared to investigator’s choice chemotherapy will also be evaluated, along with the PK and immunogenicity of odronextamab. The study will further assess the impact on patient-reported outcomes (PROs), including health-related quality of life (HRQoL), using validated instruments such as the EORTC-QLQ-C30, FACT-LymS, PGIS, PGIC, and EQ-5D-5L. Finally, the overall impact of treatment toxicity as reported by patients will be evaluated using the GP5 item of the FACT-G questionnaire.

The clinical trial involves a total of **245 participants** diagnosed with **follicular lymphoma**, specifically cluster of differentiation 20^+ (CD20^+) FL Grade 1-3a, stage II bulky or stage III/IV. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their need for treatment and the presence of measurable disease as confirmed by diagnostic imaging such as CT or MRI. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care. Additionally, adequate bone marrow and hepatic function are necessary for inclusion. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are in a general health status that allows for the assessment of the safety, tolerability, and efficacy of odronextamab compared to investigator’s choice chemotherapy.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy and safety of **odronextamab** compared to the investigator's choice of chemotherapy in participants with previously untreated **follicular lymphoma**. The trial is structured into two parts: Part 1 focuses on assessing the safety, tolerability, and dose-limiting toxicities of odronextamab, while Part 2 aims to compare the efficacy of odronextamab against the investigator's choice of chemotherapy, with the primary endpoint being the complete response at 30 months as assessed by independent central review.

The trial is expected to commence recruitment on June 30, 2023, and is estimated to conclude by December 3, 2028. Participants will be involved in the study for a maximum treatment period of 856 to 898 days, depending on the specific treatment regimen. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as CD20^+ follicular lymphoma diagnosis, measurable disease, and adequate organ function; regular follow-up visits to monitor treatment response and adverse events; and an end-of-study visit to assess the final outcomes and gather data on long-term safety and efficacy.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will utilize a variety of chemotherapy agents, including **bendamustine hydrochloride**, **doxorubicin hydrochloride**, **vincristine sulfate**, **prednisone**, **rituximab**, and **cyclophosphamide**, administered through various routes such as intravenous infusion and oral administration. The trial will also monitor secondary endpoints, including progression-free survival, event-free survival, and overall survival, to provide a comprehensive evaluation of the treatment's impact on patient outcomes.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Odronextamab**, a concentrate for solution for infusion, is the primary investigational product. It is administered via **intravenous infusion** with a maximum daily dose of 320 mg and a total dose of 320 mg. The treatment period for odronextamab is up to 856 days. This bispecific monoclonal antibody targets CD20 and CD3, and is designated as an orphan drug for the treatment of follicular lymphoma.

**Bendamustine Hydrochloride** is used as a comparator treatment in the study. It is provided as a solution for injection and administered through **intravenous infusion**. The maximum daily and total dose is 90 mg/m², with a treatment period extending up to 898 days. This chemotherapeutic agent is part of the standard-of-care therapy for certain lymphomas.

**Doxorubicin Hydrochloride** is another comparator treatment, available as a solution for injection. It is administered intravenously with a maximum daily and total dose of 50 mg/m². The treatment duration is up to 856 days. Doxorubicin is a well-established chemotherapeutic agent used in various cancer treatments.

**Vincristine Sulfate** is administered as an injection with a maximum daily and total dose of 1.4 mg/m². The treatment period is up to 856 days. Vincristine is a chemotherapy medication used to treat various types of cancer, including lymphomas.

**Prednisone** is provided in tablet form and administered orally. The maximum daily and total dose is 100 mg, with a treatment period of up to 856 days. Prednisone is a corticosteroid used in combination with other chemotherapy agents to treat lymphomas.

**Rituximab** is available in two formulations: Truxima 100 mg and Truxima 500 mg concentrates for solution for infusion. Both are administered intravenously with a maximum daily and total dose of 375 mg/m². The treatment period extends up to 898 days. Rituximab is a monoclonal antibody used in the treatment of certain types of lymphoma.

**Cyclophosphamide** is provided as a solution for injection/infusion and administered as a solution for infusion. The maximum daily and total dose is 750 mg/m², with a treatment period of up to 868 days. Cyclophosphamide is a chemotherapy agent used in combination regimens for lymphoma treatment.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study aims to compare the efficacy and safety of odronextamab against the investigator's choice of chemotherapy in previously untreated participants with 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 trial is the **Complete Response at 30 months (CR30)**, which will be evaluated by an independent central review. This endpoint is crucial for determining the effectiveness of **odronextamab** compared to the investigator's choice of chemotherapy in participants with previously untreated follicular lymphoma.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of efficacy. These include **Progression-Free Survival (PFS)** and **Event-Free Survival (EFS)**, both assessed by independent central review and local investigators. Additionally, the trial will measure **Overall Survival (OS)**, **Objective Response**, and **Duration of Response (DOR)**, with evaluations conducted by both independent central review and local investigators. The trial will also assess the **Time to Next Anti-Lymphoma Treatment (TTNT)** and the incidence and severity of treatment-emergent adverse events (TEAEs).

Patient-reported outcomes (PROs) will be measured using validated instruments such as the **European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC-QLQ-C30)**, **Functional Assessment of Cancer Therapy–Lymphoma (FACT-LymS)**, **Patient Global Impression of Severity (PGIS)**, **Patient Global Impression of Change (PGIC)**, and **EuroQol-5 Dimension-5 Level Scale (EQ-5D-5L)**. These instruments will help assess the overall mean changes in scores of PROs, providing insights into the impact of treatment on patients' quality of life.

The trial will also monitor the concentrations of odronextamab in serum during both the induction and maintenance periods, as well as the incidence and titer of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to odronextamab over the study duration. These assessments will be conducted at specified intervals throughout the trial to ensure a thorough evaluation of the drug's efficacy and safety profile.