ZUMA-12: A Phase 2 Multicenter Study of Axicabtagene Ciloleucel as a First-Line Therapy in Patients With High-Risk Large B Cell Lymphoma

Purpose of the Study: Patients with large B cell lymphoma (LBCL) who have persistent disease assessed by dynamic positron emission tomography after rituximab-based induction therapy have an increased risk of death (Blood. 2017;130:1315). Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen recep- tor (CAR) T cell therapy approved for the treatment of patients with relapsed/refractory LBCL with 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 91% (70% complete response rate) in patients with double-expressor or high-grade LBCL with ongoing responses in 48% after a median follow-up of 27.1 months (Lancet Oncol. 2019;20:31). Furthermore, patients with fewer prior lines of therapy and lower tumor burden had higher rates of ongoing responses and manageable safety (J Clin Oncol. 2018;36[suppl, abstr]:3039). In ZUMA-12, the efficacy and safety of axi-cel as a first- line therapy in newly diagnosed patients who have high-risk LBCL and positron emission tomography-positive disease after 2 cycles of induction therapy will be investigated.

Summarized Description of the Project: This Phase 2 study has a planned enrollment of 40 patients aged 18 years with high-risk LBCL, defined by the presence of MYC and BCL2 and/or BCL6 transloca- tions by fluorescent in situ hybridization or an international prognostic index score of 3 any time before enrollment, and an Eastern Coopera- tive Oncology Group performance status of 0 to 1. Before enrollment, patients must have a Deauville score of 4 to 5 (J Clin Oncol. 2014;32:3048) after 2 cycles of chemoimmunotherapy that includes an anti-CD20 monoclonal antibody and anthracycline. After leukapheresis, patients with bulky or rapidly progressing disease may receive optional nonchemotherapy bridging therapy. After condition- ing therapy with cyclophosphamide (500 mg/m2) and fludarabine  (30 mg/m2) for 3 days, patients will receive a single infusion of axi-cel at a target dose of 2 × 106 CAR T cells/kg. The primary endpoint is investigator-assessed complete response rate per the Lugano classifi- cation (J Clin Oncol. 2014;32:3059). Key secondary endpoints include objective response rate, duration of response, event-free survival, progression-free survival, overall response, safety, relapse with central nervous system disease, and levels of blood CAR T cells and serum cytokines over time. Patient accrual for ZUMA-12 is currently ongoing.