Phase 3 Randomized Study of Tafasitamab, Lenalidomide, and Rituximab in Relapsed/Refractory Follicular and Marginal Zone Lymphoma

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled, multicenter study is to compare the **efficacy** of tafasitamab and lenalidomide in addition to rituximab to the efficacy of placebo and lenalidomide in addition to rituximab in participants with relapsed/refractory (R/R) follicular lymphoma (FL). This comparison is clinically relevant as it aims to determine the potential benefit of adding tafasitamab to the existing treatment regimen, which could lead to improved therapeutic outcomes for patients with R/R FL, a condition characterized by frequent relapses and resistance to standard therapies.

Secondary objectives include:

• Comparing the efficacy of tafasitamab and lenalidomide in addition to rituximab versus placebo and lenalidomide in addition to rituximab in the overall population, which includes both FL and marginal zone lymphoma (MZL) patients.
• Evaluating the efficacy in terms of PET-CR rate in FDG-avid FL participants and overall survival (OS) in the FL population. These secondary objectives aim to provide a broader understanding of the treatment's impact across different lymphoma subtypes and specific patient groups, potentially guiding more personalized treatment approaches.

The clinical trial involves a total of **309 participants** diagnosed with **follicular lymphoma (FL)** and **marginal zone lymphoma (MZL)**. The study population includes both male and female subjects who are at least 18 years of age. Participants have a histologically confirmed Grade 1, 2, or 3a FL or nodal, splenic, or extranodal MZL. All participants have been previously treated with at least one prior systemic anti-CD20 immunotherapy or chemo-immunotherapy, such as rituximab monotherapy or chemotherapy plus immunotherapy with rituximab or obinutuzumab. The trial population was selected based on their documented relapsed, refractory, or progressive disease status following systemic therapy. The study does not specify any particular lifestyle considerations such as diet or physical activity. Both male and female subjects are included, and the trial involves a vulnerable population. The sponsor has not provided additional information regarding specific lifestyle factors or other demographic details.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **tafasitamab** plus **lenalidomide** in addition to **rituximab** versus lenalidomide in addition to rituximab in patients with relapsed/refractory **follicular lymphoma** (FL) and **marginal zone lymphoma** (MZL). The trial is conducted over an estimated duration from January 15, 2021, to January 15, 2029. Participants are expected to be involved for a maximum treatment period of 48 weeks, with the possibility of early termination if disease progression or unacceptable toxicity occurs.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological confirmation of FL or MZL and previous treatment history. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as physical examinations, laboratory tests, and imaging studies as per the Lugano 2014 criteria. The primary endpoint is progression-free survival (PFS) by investigator assessment in the FL population. Secondary endpoints include PFS in the overall population, PET-CR rate in the FDG-avid FL population, and overall survival (OS) in the FL population. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the overall outcomes of the trial.

The clinical trial involves the administration of several experimental medications, including **Revlimid** (lenalidomide), **MINJUVI** (tafasitamab), and **Truxima** (rituximab), as well as a placebo. **Revlimid** is available in hard capsule form with dosages of 5 mg, 10 mg, 15 mg, and 20 mg. The active substance, lenalidomide, is of chemical origin. The capsules are administered orally with a maximum daily dose of 20 mg and a total dose of up to 5040 mg over a treatment period of 48 weeks. The manufacturer of Revlimid is Bristol-Myers Squibb Pharma EEIG.

**MINJUVI** is provided as a 200 mg powder for concentrate for solution for infusion, containing the active substance tafasitamab, a protein of other origin. The solution is administered via intravenous infusion with a maximum daily dose of 12 mg/kg and a total dose of up to 380 mg/kg over a 48-week period. The product is manufactured by Incyte Biosciences Distribution B.V. and is designated as an orphan drug.

**Truxima** is a 100 mg concentrate for solution for infusion, containing the active substance rituximab, a protein of other origin. It is administered through intravenous infusion with a maximum daily dose of 375 mg/m² and a total dose of up to 3000 mg/m² over a treatment period of 113 weeks. The manufacturer is Celltrion Healthcare Hungary Kft.

The placebo used in the study is a 0.9% saline solution for infusion, provided in a 250 mL infusion container with 0.9% (w/v) sodium chloride for injection. This placebo is sourced locally from the commercial market and delivered to an unblinded pharmacy. The placebo is intended to mimic the administration of the active treatments without providing therapeutic effects.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of the combination of tafasitamab and lenalidomide in addition to rituximab, compared to lenalidomide and rituximab with a placebo, in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)** by investigator assessment in the follicular lymphoma (FL) population, utilizing the Lugano 2014 criteria. PFS is defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurs first. Secondary endpoints include PFS by investigator assessment in the overall population, which encompasses both FL and marginal zone lymphoma (MZL) populations, the PET-CR rate by investigator in the FDG-avid FL population, defined as a complete metabolic response at any time after the start of treatment, and overall survival (OS) in the FL population.