Phase 3 Multicenter Randomized Open-Label Trial of Epcoritamab, Rituximab, and Lenalidomide Versus Chemoimmunotherapy in Untreated Follicular Lymphoma

The primary objective of this study is to demonstrate that the combination of **epcoritamab** with rituximab and lenalidomide (ER2) will improve complete response rates at 30 months (CR30) compared to chemoimmunotherapy (CIT) in subjects with previously untreated **Follicular Lymphoma** (FL). This is clinically relevant as achieving a higher CR30 rate may indicate a more effective treatment regimen, potentially leading to better long-term outcomes for patients with FL.

Secondary objectives include: - Demonstrating that ER2 will improve progression-free survival (PFS) compared to CIT in subjects with previously untreated FL. - Demonstrating that ER2 will improve overall survival (OS) compared to CIT in subjects with previously untreated FL. - Demonstrating that ER2 will improve minimal residual disease (MRD) negativity compared to CIT in subjects with previously untreated FL. - Demonstrating that ER2 will improve the maintenance of physical functioning, using the Physical Function Subscale of the EORTC-QLQ-C30, at Week 25 compared to CIT in subjects with previously untreated FL.

The clinical trial involves a total of **549 participants** diagnosed with **Follicular 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 inclusion criteria, such as having CD20+ histologically confirmed classic follicular lymphoma, and meeting certain disease stage requirements, including stage III or IV, or stage II with bulky disease. The trial population is characterized by a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale, indicating a range from fully active to capable of all self-care but unable to carry out any work activities. Participants are required to have one or more target lesions as demonstrated by PET/CT scans. The study does not specify particular lifestyle considerations such as diet or physical activity. Both vulnerable and non-vulnerable populations are included in the trial, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized**, open-label, phase III study to evaluate the safety and efficacy of a combination therapy involving **epcoritamab**, **rituximab**, and **lenalidomide** (R2) compared to standard chemoimmunotherapy in patients with previously untreated **follicular lymphoma**. The trial aims to demonstrate an improvement in the complete response rate at 30 months (CR30) for the combination therapy group compared to the chemoimmunotherapy group. The study is expected to commence recruitment on May 1, 2024, and conclude by September 18, 2037.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of follicular lymphoma, stage III or IV disease, or stage II with bulky disease, and the presence of measurable lesions. Following the screening, eligible participants will be randomized into one of the study arms. The trial includes multiple follow-up visits to monitor safety, efficacy, and disease progression, with assessments conducted at regular intervals. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 120 weeks, with conditions for early termination including withdrawal of consent, adverse events, or disease progression. The primary endpoint is the CR30 rate, assessed by PET-CT per Lugano 2014 criteria. Secondary endpoints include progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity, and patient-reported outcomes (PROs) related to quality of life. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their safety and efficacy in patients with previously untreated **follicular lymphoma**. The experimental treatment includes **Epcoritamab (GEN3013)**, a bispecific antibody administered as a solution for injection. The pharmaceutical form is a solution for injection, and it is administered via subcutaneous injection. The maximum daily dose is 48 mg, with a total maximum dose of 1299.96 mg over a treatment period of up to 120 weeks.

**Rituximab**, marketed as Truxima, is used as a comparator treatment. It is a chimeric monoclonal antibody available as a concentrate for solution for infusion. The administration route is intravenous, with a maximum daily dose of 375 mg/m² and a total maximum dose of 7500 mg/m² over a period of 120 weeks.

**Lenalidomide**, marketed as Revlimid, is provided in two dosages: 5 mg and 20 mg hard capsules. It is administered orally with a maximum daily dose of 20 mg and a total maximum dose of 6300 mg over a treatment period of 72 weeks.

**Prednisone**, marketed as PREDNISONE BIOGARAN, is a scored tablet administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 3000 mg over 18 weeks.

**Obinutuzumab**, marketed as Gazyvaro, is a concentrate for solution for infusion administered intravenously. The maximum daily dose is 1000 mg, with a total maximum dose of 22000 mg over 120 weeks.

**Vincristine Sulfate** is provided as a 1 mg/ml solution for injection, administered intravenously. The maximum daily dose is 2.0 mg/m², with a total maximum dose of 12 mg/m² over 18 weeks.

**Doxorubicin Hydrochloride** is available as a 2 mg/ml solution for injection, administered intravenously. The maximum daily dose is 50 mg/m², with a total maximum dose of 300 mg/m² over 18 weeks.

**Cyclophosphamide** is provided as a 500 mg solution for injection, administered intravenously. The maximum daily dose is 750 mg/m², with a total maximum dose of 4500 mg/m² over 18 weeks.

**Bendamustine Hydrochloride** is available as a 100 mg powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 90 mg/m², with a total maximum dose of 1080 mg/m² over 24 weeks.

**Tocilizumab**, marketed as RoActemra, is a concentrate for solution for infusion administered intravenously. The maximum daily dose is 1600 mg, with a total maximum dose of 3200 mg over 2 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to compare the efficacy of the experimental treatment regimen with standard chemoimmunotherapy in achieving improved clinical outcomes in patients with follicular lymphoma.

The efficacy of the clinical trial will be assessed primarily through the **Complete Response** rate at 30 months (CR30) in Arm A (Epcoritamab with Rituximab and Lenalidomide, ER2) compared to Arm B (Chemoimmunotherapy, CIT). This primary endpoint will be determined using PET-CT scans evaluated according to the Lugano 2014 criteria, as assessed by an Independent Review Committee (IRC). Secondary endpoints include Progression-Free Survival (PFS) per IRC, Overall Survival (OS), Minimal Residual Disease (MRD) negativity, and patient-reported outcomes (PROs) focusing on the maintenance of the physical functioning scale of the EORTC QLQ-C30 at Week 25.