A randomized phase ii study of mb‐cart2019.1 compared to standard of care in patients with relapsed/refractory dlbcl ineligible for asct – daly 2‐eu trial

Introduction: Elderly patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) represent a distinct patient population with often limited treatment options. CAR-T cell treatment can offer a curative approach to this comorbid 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 CD20 and CD19 and is manufactured in a 12-day process, with a vein-to-vein time of 14 days. MB-CART2019.1 was introduced in a Phase I dose finding study (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. Five out of the 12 patients in the Phase I trial achieved a complete response which were durable at two-year follow-up. The favorable safety profile and encouraging early efficacy results provided the rationale for further investigation. Trial 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 to receive MB-CART2019.1 with a dose of 2.5 × 106 CAR+ T-cells per kg body weight or SoC therapy. MB-CART2019.1 is intended to be infused as a non-cropreserved product after standard lymphodepleting chemotherapy. The comparator treatment consists of R-GemOx (rituximab, gemcitabine and oxaliplatin) or Pola-BR (polatuzumab vedotin, bendamustine and rituximab). 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 1st-line chemoimmunotherapy or relapsed disease within ≤12 months from the completion of 1st-line therapy, and iii) patients ineligible for ASCT due to a HCT-CT score >3 or age ≥65 years and documented organ dysfunction or age ≥70 years. The primary endpoint of the trial is progression-free survival. In addition to safety endpoints, secondary endpoints in the experimental arm include persistence of MB-CART2019.1, phenotype and immune cell compositions. In summary, this trial (DALY 2-EU) evaluates the superiority of 2nd-line CAR-T cell treatment with MB-CART2019.1 compared to SoC in an elderly high-risk population of patients with r/r DLBC. It is planned to be performed in up to 50 clinical trial sites in 12 countries in Europe. The study is actively enrolling patients since August 2021. In addition, a separate pivotal Phase II trial in the USA is currently enrolling patients with r/r DLBCL who have failed at least two lines of prior systemic therapy (NCT04792489). The study is sponsored by Miltenyi Biomedicine Keywords: cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract. P. Borchmann Consultant or advisory role BMS, Novartis, Miltenyi Biomedicine P. Vandenberghe Consultant or advisory role Miltenyi Biomedicine Honoraria: BMS/Celgene, Kite, a Gilead Company, Novartis, Johnson & Johnson A. Urbano-Ispizua Consultant or advisory role Miltenyi Biomedicine C. Haiuon Consultant or advisory role Miltenyi Biomedicine Honoraria: BMS, Novartis, Amgen, Roche, Abbvie, Gilead L. Griškevicius Consultant or advisory role Miltenyi Biomedicine F. Lemonnier Consultant or advisory role Miltenyi Biomedicine G. Zadoyan Employment or leadership position: Miltenyi Biomedicine U. Bethke Employment or leadership position: Miltenyi Biotec T. Overstijns Employment or leadership position: Miltenyi Biomedicine L. Hanssens Employment or leadership position: Miltenyi Biomedicine I. Bürger Employment or leadership position: Miltenyi Biotec M. Assenmacher Employment or leadership position: Miltenyi Biotec O. Reer Employment or leadership position: Miltenyi Biotec B. Friedrichs Employment or leadership position: Miltenyi Biomedicine S. Holtkamp Employment or leadership position: Miltenyi Biomedicine U. Jäger Consultant or advisory role Miltenyi Biomedicine Honoraria: Roche, Novartis, Gilead, BMS Celgene M. J. Kersten Consultant or advisory role Miltenyi Biomedicine Honoraria: Roche, Novartis, Kite/Gilead, BMS/Celgene