Open-label dose-finding and dose-expansion study to evaluate the safety, expansion, persistence, and clinical activity of UCART20x22 in subjects with relapsed or refractory B-cell Non-Hodgkin Lymphoma (B-NHL)

The primary objective of this study is to evaluate the **safety** and tolerability of UCART20x22 in subjects with relapsed or refractory (R/R) mature B-cell Non-Hodgkin Lymphoma (B-NHL) during the dose-finding phase. This includes determining the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In the dose-expansion phase, the study aims to confirm the RP2D in subjects with R/R large B-cell lymphoma (LBCL). Assessing safety and determining the appropriate dosing are crucial for ensuring the therapeutic efficacy and minimizing adverse effects in patients with these aggressive lymphomas.

Secondary objectives include:

• For the Dose-Finding Part: Assessing the antitumor activity of UCART20x22 in subjects with R/R mature B-NHL.
• Identifying the optimal lymphodepletion regimen to evaluate in dose-expansion part cohort(s).
• For the Dose-Expansion Part: Assessing the antitumor activity of UCART20x22 in subjects with specific subtypes of R/R large B-cell lymphoma (LBCL).

The clinical trial involves a total of **37 participants** diagnosed with **relapsed or refractory B-cell Non-Hodgkin lymphoma**. The study population includes both male and female subjects, aged between **18 to 80 years**, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, which required adequate organ function, a negative serologic or PCR test for hepatitis B, C, and HIV, and an ECOG performance status of 0 or 1. Additionally, women of childbearing potential were required to have a negative pregnancy test prior to enrollment. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must have relapsed or refractory disease after at least two lines of prior treatment, including specific therapies depending on the lymphoma subtype, and must have at least one measurable lesion according to the Lugano Response Criteria for Malignant Lymphoma. The selection process ensures that participants have resolved prior treatment-related toxicities to baseline or Grade 1 before starting the LD regimen.

The clinical trial is designed to evaluate the safety, expansion, persistence, and clinical activity of **UCART20x22** in subjects with relapsed or refractory B-cell Non-Hodgkin Lymphoma (B-NHL). This trial is structured as an open-label, dose-finding, and dose-expansion study. The trial is not categorized as low intervention and is conducted in two parts: dose-finding and dose-expansion. The primary objective for the dose-finding part is to assess the safety and tolerability and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of UCART20x22. For the dose-expansion part, the objective is to confirm the RP2D and further assess safety and tolerability. The trial is expected to conclude by November 2041, with recruitment having started in January 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and disease status. Follow-up visits will be scheduled to monitor safety and efficacy, with assessments including the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs). The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any remaining safety concerns are addressed. The expected length of participant involvement will vary depending on individual response and the specific part of the trial they are enrolled in. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicity, withdrawal of consent, or any other reason deemed necessary by the investigator.

The trial employs a randomized, controlled design, with participants receiving the investigational product via **intravenous** administration. The study will assess primary endpoints such as the incidence and severity of AEs and SAEs, as well as dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR), evaluated according to the Lugano response criteria. The trial will also monitor host T-cell recovery and CAR T-cell expansion, providing comprehensive data on the investigational product's antitumor activity and safety profile.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **ENDOXAN 1000 mg**, containing the active substance **cyclophosphamide**, is provided as a powder for solution for injection. It is administered intravenously. The pharmaceutical form is a solution for injection, and the product is manufactured by Baxter SAS. The administration schedule and dosage are determined based on the trial protocol.

**Genoxal 1.000 mg**, containing **cyclophosphamide monohydrate**, is available as a powder for solution for injection and infusion. This product is also administered intravenously. The pharmaceutical form is a solution for injection/infusion, produced by Baxter Oncology GmbH. The dosing schedule is aligned with the trial's requirements.

**LEMTRADA 12 mg**, with the active substance **alemtuzumab**, is provided as a concentrate for solution for infusion. It is administered intravenously, with the pharmaceutical form being a solution for infusion. This product is manufactured by Sanofi Belgium, and the administration follows the trial's dosing guidelines.

**Fludarabina Teva 25 mg/ml**, containing **fludarabine phosphate**, is a concentrate for solution for infusion or injection. It is administered intravenously, with the pharmaceutical form being an injection. The product is produced by Teva Pharma S.L.U., and the dosing schedule is specified in the trial protocol.

**FLUDARA 50 mg**, also containing **fludarabine phosphate**, is available as a powder for solution for injection or infusion. It is administered intravenously, with the pharmaceutical form being a solution for injection/infusion. This product is manufactured by Genzyme Europe B.V., and the administration follows the trial's dosing instructions.

**CLLS52**, containing **alemtuzumab**, is provided as a solution for infusion. It is administered intravenously, with the pharmaceutical form being a solution for infusion. The product is manufactured by Cellectis S.A., and the dosing schedule is determined by the trial protocol.

**UCART20X22**, a cell suspension for injection, is a structurally diverse substance used in cell therapy. It is administered intravenously, with the pharmaceutical form being a cell suspension for injection. This product is manufactured by Cellectis SA, and the administration follows the trial's dosing guidelines. The trial aims to evaluate the safety, expansion, persistence, and clinical activity of UCART20X22 in subjects with relapsed or refractory B-cell Non-Hodgkin Lymphoma.

The efficacy of the clinical trial will be assessed using several parameters. The primary endpoints for the dose-finding part include the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs), as well as the proportion of subjects in each dose-level cohort experiencing dose-limiting toxicities (DLTs) during the DLT observation period. For the dose-expansion part, the primary endpoints focus on the incidence, nature, and severity of AEs and SAEs during the dose-expansion phase, including those associated with lymphodepletion (LD).

Secondary endpoints for both the dose-finding and dose-expansion parts include the investigator-assessed overall response rate (ORR) according to the Lugano response criteria, progression-free survival (PFS), overall survival (OS), and duration of response (DoR). Additionally, the trial will evaluate the incidence, nature, and severity of AEs and SAEs associated with LD, the associated antitumor activity, and the corresponding host T-cell recovery and CAR T-cell expansion.