Evaluation of Morphologic Complete Response in Early Stage Nodal Follicular Lymphoma with Rituximab or Obinutuzumab Plus Radiotherapy

The primary objective of this study is to evaluate the rate of **morphologic complete response (CR)** in week 18 following standard dose (24 Gy) involved site radiotherapy (IS RT) combined with Rituximab, or low-dose (4 Gy) IS RT in combination with Obinutuzumab, in patients with early stage nodal **follicular lymphoma**. This assessment is clinically relevant as it aims to determine the efficacy of these treatment regimens in achieving complete remission, which is a critical factor in improving patient outcomes and guiding therapeutic decisions.

Secondary objectives include:

• Assessment of morphologic CR, partial response (PR), stable disease (SD), and progressive disease (PD) at week 7 and month 6 in patients with initially remaining lymphoma, as judged by CT/MRI.
• Evaluation of metabolic CR at week 18 in patients with initially remaining lymphoma, as judged by FDG-PET/CT (centrally reviewed).
• Determination of progression-free survival (PFS) for each treatment arm, two years post individual treatment initiation.
• Analysis of PFS in patients at stage I0 post-diagnostic surgery (no remaining lymphoma) treated as the experimental arm, two years post individual treatment initiation.
• Evaluation of toxicity using NCI-CTC criteria, version 5, across all patients.
• Investigation of relapse rate and recurrence patterns for each treatment arm at all follow-up visits.
• Assessment of overall survival (OS) for each treatment arm over a two-year period.
• Evaluation of quality of life using EORTC QLQ C30 and FACTLym questionnaires at inclusion, and at week 18, month 12, and month 24 for each treatment arm.

The clinical trial involves participants diagnosed with **early stage follicular lymphoma**, specifically CD20-positive follicular lymphoma grade 1/2 or 3a, as per the WHO classification (2016). The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Participants are required to have untreated nodal follicular lymphoma, including involvement of Waldeyer's ring, and must be in clinical stage I or II according to the Ann Arbor classification based on FDG-PET staging. The trial population was selected based on specific criteria, including adequate bone marrow capacity and the ability to understand the trial's intention and consequences. The sponsor has not provided information regarding the total number of participants. The study includes individuals who are part of a vulnerable population, and participants must adhere to adequate contraception during therapy and for 18 months thereafter. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **rituximab** and **obinutuzumab** in combination with radiotherapy for patients with early-stage follicular lymphoma. This is a randomized, double-blind, controlled trial aimed at assessing the rate of morphologic complete response (CR) at week 18 following standard dose (24 Gy) involved site radiotherapy (RT) plus rituximab or low-dose (4 Gy) IS RT in combination with obinutuzumab. The trial is expected to run until September 2029, with recruitment having commenced in July 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, stage of lymphoma, and bone marrow capacity. Following the screening, participants will be randomized to receive either rituximab or obinutuzumab, both administered via intravenous infusion. The trial includes follow-up visits at week 7, month 6, and subsequent intervals to monitor morphologic CR, progression-free survival, and overall survival, among other endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 16 months, depending on the treatment arm. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will also assess secondary endpoints such as metabolic CR, toxicity, relapse rate, and quality of life using standardized questionnaires. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimens in this patient population.

The clinical trial involves the administration of **MabThera**, a **concentrate for solution for infusion** containing the active substance **rituximab**. Rituximab is a monoclonal chimeric antibody (mouse/human) classified under the ATC code **L01XC02**. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of up to 12 weeks. The product is manufactured by Roche Registration GmbH and is authorized under the marketing authorization number EU/1/98/067/002. Compliance with the dosing schedule is monitored throughout the trial.

Another experimental medication used in the trial is **Gazyvaro**, a **concentrate for solution for infusion** containing the active substance **obinutuzumab**. Obinutuzumab is a humanised monoclonal antibody, and its pharmaceutical form is also a solution for infusion, administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total maximum dose of 7000 mg over a treatment period of up to 16 weeks. This product is also manufactured by Roche Registration GmbH and is authorized under the marketing authorization number EU/1/14/937/001. Participant compliance with the dosing regimen is closely monitored during the study.

In addition to the experimental medications, the trial includes standard-of-care therapy involving radiotherapy. The objective is to evaluate the rate of morphologic complete response (CR) at week 18 following either standard dose (24 Gy) involved site radiotherapy (IS RT) plus Rituximab or low-dose (4 Gy) IS RT in combination with Obinutuzumab in patients with early-stage nodal follicular lymphoma. The trial does not utilize a placebo or comparator treatment, focusing solely on the efficacy of the experimental medications in conjunction with radiotherapy.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of **morphologic complete response (CR)** at week 18 in patients with remaining macroscopic PET-positive lymphoma after the initial diagnostic biopsy, as judged by CT and centrally reviewed. Secondary endpoints include morphologic CR, partial response (PR), stable disease (SD), and progressive disease (PD) at week 7 and month 6, evaluated by CT/MRI. Additionally, metabolic CR at week 18 will be assessed using FDG-PET/CT, also centrally reviewed.

Progression-free survival (PFS) will be measured for each treatment arm two years after the individual treatment start, as well as for patients in stage I0 after diagnostic surgery treated as the experimental arm. Other secondary endpoints include toxicity assessed by NCI-CTC criteria version 5, relapse rate and pattern of recurrence at all follow-up visits, overall survival (OS) of each treatment arm over two years, and quality of life evaluated using EORTC QLQ C30 and FACT-Lym questionnaires at inclusion and at week 18, month 12, and month 24 for each treatment arm.