A Phase 2, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination with Either Rituximab or Lenalidomide in Patients with Refractory Large B-Cell Lymphoma (ZUMA-14)

Background: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adult patients who have relapsed/refractory large B cell lymphoma (LBCL) and have had ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 83% (complete response rate, 58%), with ongoing responses in 39% after a median follow-up of 27.1 months (Locke FL, et al. Lancet Oncol. 2019). Despite the success of axi-cel, approximately 60% of patients have no response or relapse after treatment, indicating that additional strategies are needed for patients with relapsed/refractory LBCL. Preclinical murine studies have shown that rituximab augmented the tumor-suppressing effects of anti-CD19 CAR T cells, and the combination led to higher rates of tumor reduction (Mihara K, et al. Br J Haematol. 2010; Rufener GA, et al. Cancer Immunol Res. 2016). The IMiD® immunomodulatory agent lenalidomide has shown activity in patients with relapsed/refractory diffuse large B cell lymphoma and has also been shown to enhance the antitumor functions of anti-CD19 and anti-CD20 CAR T cells in mice (Otahal P, et al. Oncoimmunology. 2016). In ZUMA-14, the aim is to investigate the efficacy and safety of axi-cel in combination with rituximab or lenalidomide in adult patients with refractory LBCL.

Methods: This Phase 2 study (NCT04002401) has a planned enrollment of approximately 60 patients aged ≥ 18 years with refractory LBCL, defined as a response of either progressive disease or stable disease to previous chemotherapy or progressive disease or relapse ≤ 12 months after an autologous stem cell transplant. Patients with prior IMiD® treatment, including lenalidomide, prior CAR T cell therapy, and/or prior CD19-targeted therapy are excluded. After leukapheresis, patients will be assigned 1:1 to receive axi-cel with either rituximab (Cohort 1) or lenalidomide (Cohort 2). Patients will receive lymphodepleting chemotherapy of fludarabine (30 mg/m²) and cyclophosphamide (500 mg/m²) on days -5 to -3 before axi-cel infusion (2 × 10⁶ cells/kg) on Day 0. Cohort 1 will receive rituximab (375 mg/m²) every 28 days starting on Day -5 for a total of 6 doses. Cohort 2 will receive lenalidomide (10 mg) daily starting 7 days after leukapheresis through Day 3 and for 5 additional cycles (20 mg, first 21 days of each 28-day cycle) beginning after axi-cel infusion starting on Day 21. Patients may not receive any therapy other than conditioning therapy and rituximab or lenalidomide, as specified by cohort, between leukapheresis and axi-cel infusion. The primary endpoint is investigator-assessed complete response rate per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints include safety, objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (levels of blood CAR T cells over time). Exploratory endpoints for both cohorts include pharmacodynamic assessment of cytokine profiles and the rate of CD19-negative relapses. An additional exploratory endpoint for Cohort 2 is to investigate immunomodulation of the tumor microenvironment, including the number and activation of T cells and natural killer cells. Enrollment is expected to start in September 2019.