Trial in Progress: A Randomized Phase II Study of MB-CART2019.1 Compared to Standard of Care Therapy in Patients with Relapsed/Refractory DLBCL Ineligible for High-Dose Chemotherapy and Autologous Stem Cell Transplantation - DALY 2-EU Trial (2022)

Background: Elderly patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) who are not candidates for autologous stem cell transplantation (ASCT) have poor outcomes. Chimeric antigen receptor (CAR) T cell treatment can offer a curative approach to this patient population, but data directly comparing standard chemotherapy with CAR-T cell therapy are scarce. MB-CART2019.1 (Zamtocabtagene autoleucel) is a tandem CAR-T cell product targeting the CD20 and CD19 antigens and has shown superior efficacy as compared to each single-CAR in pre-clinical models. MB-CART2019.1 is manufactured in a 13-day process and consists of autologous CD4 and CD8 enriched T-cells, transduced with a lentiviral vector encoding a CAR construct combining CD20 and CD19 single chain variable fragments and incorporating 4-1BB and CD3ζ signaling domains. MB-CART2019.1 was introduced in a Phase I dose finding study (DALY 1, NCT03870945) in mainly elderly patients with r/r B-cell lymphoma. It demonstrated encouraging safety with a low incidence of neurotoxicity and cytokine release syndrome, all of which were Grade 1 or 2. Five out of the 12 patients in the Phase I trial achieved a complete response (CR) by positron emission tomography-computerized tomography (PET-CT). Two-year follow-up data reveals that all 5 CRs were durable without evidence of relapse as per investigator assessment. The favorable safety profile and encouraging early efficacy results provided the rationale for the development of this Phase II trial in an elderly r/r DLBCL patient cohort with limited curative treatment options. Study Design and Methods: This study is a pivotal Phase II randomized, multi-center, open-label study comparing the efficacy and safety of MB-CART2019.1 to standard of care (SoC) therapy in participants with r/r diffuse large B-cell lymphoma who are not eligible for high-dose chemotherapy (HDC) and ASCT (Clinical trial information: NCT04844866). A total of 168 adult patients with r/r DLBCL will be randomized in a 1:1 ratio to receive MB-CART2019.1 or SoC therapy. In the experimental arm, patients are treated with a dose of 2.5 × 106 CAR+ T-cells per kg body weight based on the recommended dose in the Phase I trial. MB-CART2019.1 is manufactured without freeze-thaw cycles and intended to be infused as a fresh product (day 0) after lymphodepleting chemotherapy with fludarabine 30 mg/m2body surface area (BSA)/d and cyclophosphamide 300 mg/m2 BSA/d on day -5 to day -3 prior to MB-CART2019.1 infusion. The comparator treatment consists of R-GemOx (rituximab, gemcitabine and oxaliplatin) or Pola-BR (polatuzumab vedotin, bendamustine and rituximab), pre-defined to a maximum of 10% of enrolled patients. Main criteria for inclusion are i) histologically proven DLBCL and associated subtypes, according to the WHO 2016 classification ii) patients with either refractory disease after first-line chemoimmunotherapy or relapsed disease within ≤12 months from the completion of first-line therapy, and iii) patients ineligible to receive HDC followed by ASCT due to a HCT-CT score >3 or age ≥65 years and documented organ dysfunction. The primary endpoint of the trial is progression-free survival. Key secondary endpoints include event-free survival, best complete response rate, duration of response and overall survival. Secondary endpoints in the experimental arm include persistence of MB-CART2019.1, phenotype and immune cell compositions, and anti-MB-CART2019.1 antibodies. Safety endpoints include frequency and severity of adverse events as well as the use of tocilizumab and/or high-dose steroids. PET-CTs are performed for response will be assessed by an Independent Review Committee according to the Lugano 2014 criteria. In summary, this trial (DALY 2-EU) evaluates the superiority of second-line CAR-T cell treatment with MB-CART2019.1 compared to SoC in an elderly high-risk population of patients with r/r DLBCL and early relapse. It is planned to be performed in up to 50 clinical trial sites in 10 countries in Europe. The study is actively enrolling patients since August 2021. In addition, MB-CART2019.1 is under development in the United States, and a separate pivotal Phase II trial is currently enrolling patients with r/r DLBCL who have failed at least two lines of prior systemic therapy (DALY 2.0 USA, NCT04792489).