A Phase 3 Randomized Study Comparing Odronextamab and Lenalidomide Versus Rituximab and Lenalidomide in Relapsed/Refractory Follicular and Marginal Zone Lymphoma

The primary objective of this Phase 3, open-label, randomized study is to assess the **safety**, tolerability, and dose-limiting toxicities of **odronextamab** in combination with lenalidomide in participants with relapsed/refractory (R/R) indolent lymphoma, specifically follicular lymphoma (FL) and marginal zone lymphoma (MZL). Additionally, the study aims to compare the efficacy of odronextamab combined with lenalidomide versus rituximab combined with lenalidomide (R2) in participants with R/R FL and subsequently in those with indolent lymphoma, as measured by progression-free survival (PFS) per independent central review. This is clinically relevant as it seeks to establish a potentially more effective treatment regimen for these lymphoma subtypes, which are often challenging to treat due to their relapsed or refractory nature.

Secondary objectives include: - Part 1: Characterizing the pharmacokinetics (PK) of odronextamab, assessing its immunogenicity, and evaluating its preliminary anti-tumor activity in participants with R/R indolent lymphoma. - Part 2: Comparing the efficacy of odronextamab in combination with lenalidomide versus R2, as measured by endpoints such as complete response (CR), best overall response (BOR), and overall survival (OS). Additional measures of efficacy, safety, and tolerability of the combination therapy are also assessed. Furthermore, the study evaluates the PK and immunogenicity of odronextamab, as well as the impact on patient-reported outcomes, including health-related quality of life, functioning symptoms, general health status, and the overall impact of treatment toxicity.

The clinical trial involves a total of **238 participants** diagnosed with **relapsed/refractory follicular lymphoma** or **relapsed/refractory marginal zone lymphoma (MZL)**. 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 local histologic confirmation of the disease and a history of refractory or relapsed conditions following at least one prior line of systemic chemo-immunotherapy or immunotherapy. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are ambulatory and capable of self-care. Additionally, participants must have adequate hematologic and organ function. Lifestyle considerations include an understanding of the potential teratogenic risk of lenalidomide, with participants agreeing to abstain from blood donation during and after the study drug therapy and to adhere to pregnancy precautions. The trial does not focus on any specific dietary or physical activity requirements.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of **odronextamab** in combination with **lenalidomide** compared to **rituximab** in combination with lenalidomide in participants with relapsed/refractory follicular lymphoma and marginal zone lymphoma. The trial is structured in two parts: Part 1 is a safety run-in phase to assess the safety, tolerability, and dose-limiting toxicities of odronextamab with lenalidomide, while Part 2 is a randomized phase to compare the efficacy of the two treatment combinations. The primary endpoint for Part 1 includes the incidence of dose-limiting toxicities and treatment-emergent adverse events, while Part 2 focuses on progression-free survival as assessed by independent central review. Secondary endpoints include odronextamab concentrations in serum, incidence of anti-drug antibodies, and overall survival, among others.

The trial is expected to last until April 2029, with participant recruitment starting in June 2023. Participants will be involved in the study for a maximum treatment period of 48 weeks. The study includes several visits: an initial screening visit to confirm eligibility based on criteria such as histologic confirmation of the disease, prior treatment history, and adequate organ function. Follow-up visits will be conducted to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. Participants may be terminated early from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for their safety.

**Odronextamab** is an experimental medication used in this clinical trial. It is a **concentrate for solution for infusion** and is administered via the **intravenous** route. The maximum daily dose is 320 mg, with a total treatment period of up to 48 weeks. Odronextamab is a bispecific monoclonal antibody targeting CD20 and CD3, and it is produced by Regeneron Pharmaceuticals, Inc. The medication is not formulated for pediatric use and has been designated as an orphan drug for this study.

**Truxima**, containing the active substance **rituximab**, is used as a comparator treatment in this study. It is available in two formulations: a 100 mg and a 500 mg concentrate for solution for infusion. Both formulations are administered intravenously. The maximum daily dose is 375 mg/m², with a treatment duration of up to 48 weeks. Truxima is a monoclonal antibody targeting CD20, produced by Celltrion Healthcare Hungary Kft. It is not a pediatric formulation and does not have orphan drug status in this trial.

**Lenalidomide** is used as an auxiliary treatment in combination with both experimental and comparator medications. It is provided in the form of **hard capsules** and is administered orally. The maximum daily dose is 20 mg, with a treatment period of up to 48 weeks. Lenalidomide is a chemical substance and is not formulated for pediatric use. It does not have orphan drug status in this study.

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 **progression-free survival (PFS)**, which will be evaluated by an independent central review in participants with relapsed/refractory follicular lymphoma (FL) and indolent lymphoma, including marginal zone lymphoma (MZL). Secondary endpoints include various measures such as the concentration of odronextamab in serum, incidence and titer of anti-drug antibodies (ADA), and neutralizing antibodies (NAbs) to odronextamab over the study duration. Additionally, the best overall response (BOR), duration of response (DOR), and complete response (CR) will be assessed by both investigator review and independent central review.

Other secondary endpoints include overall survival (OS), event-free survival (EFS), and time to next anti-lymphoma treatment (TTNT). The incidence and severity of treatment-emergent adverse events (TEAEs) for odronextamab in combination with lenalidomide versus rituximab in combination with lenalidomide (R2) will also be evaluated. Patient-reported outcomes (PROs) will be measured using validated instruments such as the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQC30), Functional Assessment of Cancer Therapy–Lymphoma Subscale (FACT-LymS), Patient Global Impression on Severity (PGIS), Patient Global Impression on Change (PGIC), and EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L). The overall change in scores of these PROs will be analyzed to assess the impact on quality of life. The trial is designed to provide comprehensive data on the efficacy of the treatment regimens under investigation.