Phase II Randomized Study of MB-CART2019.1 Versus Standard Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for High-Dose Chemotherapy

The primary objective of this study is to determine the superiority of **MB-CART2019.1** treatment compared to standard of care (SoC) therapy with R-GemOx (rituximab, gemcitabine, and oxaliplatin) in terms of event-free survival in second-line therapy for participants with relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL) who are not eligible for high-dose chemotherapy and autologous stem cell transplantation. This is clinically relevant as it addresses a critical need for effective treatment options in a patient population with limited alternatives.

Secondary objectives include:

• Evaluating the efficacy of MB-CART2019.1 compared to SoC therapy.
• Assessing the safety and toxicity of MB-CART2019.1 in comparison to SoC therapy.
• Evaluating changes in health-related quality of life (HRQoL) and lymphoma symptoms in participants receiving MB-CART2019.1 compared to SoC therapy.
• Assessing the humoral immunogenicity against MB-CART2019.1.

The clinical trial involves participants diagnosed with **relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL)**. The study population includes both male and female subjects, aged 18 years and older, who are considered a vulnerable population. Participants were selected based on their ineligibility for high-dose chemotherapy and autologous stem cell transplantation, as assessed by their treating physician. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are required to have a histologically confirmed diagnosis of DLBCL and must have relapsed or refractory disease following first-line chemoimmunotherapy. Lifestyle considerations such as the use of highly effective contraceptive measures are mandated for women of childbearing potential and men with non-pregnant partners. The trial population is expected to comply with all study-related procedures and have an estimated life expectancy of more than three months for reasons other than the primary disease. The sponsor has not provided additional details regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is a pivotal Phase II, randomized, multi-center, open-label study designed to evaluate the efficacy and safety of **MB-CART2019.1** compared to standard of care therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL) who are not eligible for high-dose chemotherapy and autologous stem cell transplantation. The trial aims to determine the superiority of MB-CART2019.1 treatment in terms of event-free survival as the primary endpoint, with secondary endpoints including progression-free survival, best complete response rate, duration of complete response, and overall survival. The study is expected to conclude by March 31, 2030, with recruitment having started on July 26, 2021.

Participants will be involved in the study for a maximum treatment period of 12 months, depending on the treatment arm. The trial includes a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven DLBCL, age ≥ 18 years, and measurable disease according to Lugano criteria. Follow-up visits will be conducted to monitor treatment response and safety, with assessments based on independent review committee evaluations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience disease progression, fail to achieve a partial or complete response by Week 8, or require a new anti-lymphoma therapy. Additionally, participants may be withdrawn if they are unable to comply with study procedures or if the investigator deems it necessary for safety reasons. The trial involves the administration of investigational products via intravenous infusion, with the primary investigational product being MB-CART2019.1, a cell therapy product, and the comparator being a combination of rituximab, gemcitabine, and oxaliplatin.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Oxaliplatin** is administered as an intravenous infusion with a pharmaceutical form designated as PHF00230MIG. The maximum daily dose is 100 mg/ml, with a total maximum dose of 800 mg/ml over a treatment period of up to 8 weeks. The packaging is over-labeled with a clinical trial label on both primary and secondary packaging.

**Gemcitabine Hydrochloride** is also administered via intravenous infusion, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 1000 mg/m², and the total maximum dose is 8000 mg/m² over a treatment period of up to 8 weeks. The product is unpacked from the commercial carton and repackaged into five separate new cartons, with clinical trial labeling applied.

**Fludarabine** is administered through intravenous administration, with a pharmaceutical form of PHF675. The maximum daily dose is 30 mg/m², with a total maximum dose of 90 mg/m² over a treatment period of up to 3 weeks. No changes to the original packaging are noted.

**Bendamustine Hydrochloride** is given as an intravenous infusion, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 90 mg/ml, and the total maximum dose is 1080 mg/ml over a treatment period of up to 12 weeks. The product is unpacked from the commercial carton and repackaged into five separate new cartons, with clinical trial labeling applied.

**Zamtocabtagene Autoleucel**, marketed as MB-CART2019.1, is administered via intravenous infusion. The maximum daily and total dose is 2,500,000 U/ml, with a treatment period of 1 week. This product is an orphan drug and is provided in its original infusion form.

**Polatuzumab Vedotin** is administered as an intravenous infusion, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 1.8 mg/ml, with a total maximum dose of 10.80 mg/ml over a treatment period of up to 6 weeks. The packaging is over-labeled with a clinical trial label on both primary and secondary packaging.

**Rituximab** is administered via intravenous infusion, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 375 mg/ml, and the total maximum dose is 3000 mg/ml over a treatment period of up to 12 weeks. The packaging is over-labeled with a clinical trial label on both primary and secondary packaging.

**Anhydrous Cyclophosphamide** is administered through intravenous administration, with a pharmaceutical form of PHF00231MIG. The maximum daily dose is 300 mg/m², with a total maximum dose of 900 mg/m² over a treatment period of up to 3 weeks. No changes to the original packaging are noted.

**Tocilizumab** is administered as an intravenous infusion, with a pharmaceutical form of PHF00231MIG. The maximum daily dose is 2400 mg, with a total maximum dose of 3200 mg over a treatment period of up to 2 weeks. No changes to the original packaging are noted.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial also includes a standard-of-care therapy, R-GemOx, which consists of rituximab, gemcitabine, and oxaliplatin, serving as a comparator treatment to evaluate the efficacy of MB-CART2019.1 in participants with relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL).

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Event-free survival (EFS)**, which is defined as the time from randomization to the occurrence of objective disease progression, failure to achieve partial response (PR) or complete response (CR) at or beyond Week 8, initiation of new anti-lymphoma therapy, or death from any cause, whichever occurs first. This will be evaluated based on the assessment by an independent review committee (IRC).

Secondary endpoints include **Progression-free survival (PFS)**, which measures the time from randomization to disease progression or death from any cause, and **Best complete response rate (BCRR)**, which is the proportion of participants achieving at least one CR assessment by Week 24 in the MB-CART2019.1 arm and Week 26 in the comparator arm, both assessed by the IRC. Additionally, **Duration of complete response (DOCR)** will be evaluated as the time from the first CR to disease progression or death, and **Overall survival (OS)**, defined as the time from randomization to death from any cause.