Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-Bcma CAR T Cell Therapy

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect.

Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 10⁶ CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood.

Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks (<1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10^-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 10⁶ CAR+ T cells.

Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses.