Phase II Study of Rituximab, Lenalidomide, and Tafasitamab in High-Risk Follicular Lymphoma and Rituximab, Lenalidomide with Tafasitamab Randomization in Low-Risk Cases

The primary objective of this phase II study is to assess the **efficacy** of adding tafasitamab to the rituximab-lenalidomide regimen in the primary treatment of **follicular lymphoma**. This evaluation is clinically relevant as it aims to determine whether the addition of tafasitamab can enhance treatment outcomes for patients with this type of lymphoma, potentially offering a more effective therapeutic option.

Secondary objectives include:

• Further assessments of the efficacy of the addition of tafasitamab to rituximab-lenalidomide.
• Comparing the **safety** profile of the combination of tafasitamab with rituximab-lenalidomide versus rituximab-lenalidomide alone.
• Evaluating the quality of life (QoL) of patients receiving tafasitamab in combination with rituximab-lenalidomide compared to those receiving rituximab-lenalidomide alone.

The clinical trial focuses on evaluating the efficacy of adding tafasitamab to rituximab-lenalidomide in the primary treatment of **follicular lymphoma**. The study population includes both male and female participants aged between 18 and 85 years, with a histologically confirmed diagnosis of follicular lymphoma (excluding grade 3B) at stages II-IV, who are not suitable for radiotherapy. Participants must have at least one two-dimensionally measurable lesion with a longest diameter greater than 15 mm and a WHO performance status of 0-2. The trial includes individuals with at least one treatment indication such as symptomatic disease, vital organ or vascular compression, or bulky disease, among others. The trial population was selected based on these criteria, and participants are required to provide written informed consent according to ICH-GCP guidelines. The sponsor has not provided information regarding the total number of participants. Both genders are included, and the study considers lifestyle factors such as the use of effective contraception methods for women of child-bearing potential and sexually active male participants to prevent exposure to study drugs. The trial also involves a vulnerable population, ensuring comprehensive safety and ethical considerations.

The clinical trial is designed to evaluate the efficacy of adding **tafasitamab** to a treatment regimen of **rituximab** and **lenalidomide** for patients with **follicular lymphoma**. This is a phase II, randomized, double-blind, controlled study. The trial will involve a 1:1 randomization for low-risk patients to receive either the combination of rituximab and lenalidomide or the addition of tafasitamab. High-risk patients will receive all three drugs. The study is expected to conclude by December 31, 2030, with recruitment starting on May 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of follicular lymphoma, and performance status. Following the screening, participants will be randomized and begin treatment. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.

The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of 50 weeks for those receiving tafasitamab. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is event-free survival at 24 months (EFS24), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and safety assessments based on adverse event incidence and severity.

The clinical trial involves the administration of **Rituximab**, a monoclonal antibody used in the treatment of follicular lymphoma. Rituximab is provided as a **solution for infusion** and is administered **intravenously**. The dosage is calculated based on body surface area, with a maximum daily and total dose of **375 mg/m²**. The treatment period for Rituximab is up to **24 weeks**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

**Tafasitamab**, marketed as Minjuvi, is another experimental medication used in this study. It is supplied as a **powder for concentrate for solution for infusion** and is also administered via **intravenous infusion**. The dosing regimen for Tafasitamab is based on body weight, with a maximum daily and total dose of **12 mg/kg**. The treatment duration for Tafasitamab extends up to **50 weeks**. The administration of Tafasitamab is closely monitored to ensure proper dosing and participant compliance.

**Lenalidomide** is included in the trial as a **hard capsule** for **oral** administration. The maximum daily and total dose for Lenalidomide is **15 mg**, with a treatment period of up to **27 weeks**. Participants are required to adhere to the oral dosing schedule, and compliance will be assessed regularly to maintain the integrity of the study.

In this trial, the combination of Rituximab, Lenalidomide, and Tafasitamab is being evaluated for its efficacy in the primary treatment of follicular lymphoma. The study design includes a 1:1 randomization for low-risk disease participants to receive either the combination therapy or Rituximab and Lenalidomide alone. The trial aims to assess the potential benefits of adding Tafasitamab to the standard treatment regimen.

The efficacy of the treatment regimen in the clinical trial for follicular lymphoma will be assessed using a combination of primary and secondary endpoints. The primary endpoint is Event-Free Survival at 24 months (EFS24), which is defined as the interval between the start of treatment and the occurrence of disease progression, initiation of new lymphoma treatment, or death, whichever occurs first, within two years of study entry.

Secondary endpoints include several measures: Event-Free Survival (EFS), Progression-Free Survival (PFS), Progression of Disease at 24 months (POD24), Overall Survival (OS), Overall Response Rate (ORR), Complete Response Rate (CRR), Lymphoma-Specific Survival (LSS), time to next treatment, duration of response, incidence of transformation, and safety based on the incidence and severity of adverse events (AEs). Additionally, Health-Related Quality of Life (HR-QoL) will be measured using the EORTC QLQ-C30 instrument.

The efficacy parameters will be collected and analyzed at specified intervals throughout the trial, with the primary focus on the two-year mark for EFS24. The analysis will involve comparing the intervals from treatment initiation to the defined events for each endpoint. The safety profile will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, focusing on the frequency and duration of grade 3-5 treatment-related AEs.