ALACRITY: A phase 1b/2 study of AZD0120 (BCMA/CD19 CAR-T cell therapy) in participants with relapsed or refractory light chain amyloidosis (AL)

Abstract Background Light chain amyloidosis (AL) is a rare, progressive plasma cell (PC) disorder marked by misfolding and organ deposition of monoclonal immunoglobulin light chains as amyloid fibrils. It has substantial morbidity and mortality; ~40% of patients die within 1y of diagnosis (Sabinot et al. Blood Rev 2023). Daratumumab+CyBorD (cyclophosphamide, bortezomib, dexamethasone) is approved to treat newly diagnosed AL (ANDROMEDA study), with improved outcomes. Yet ~1/3 patients on first-line daratumumab+CyBorD fail to respond adequately and need second-line therapy within a median follow-up of 22 months (Bazarbachi et al. Am J Hematol 2024). Currently no approved therapies for relapsed or refractory (R/R) AL exist. Off-label approaches show sub-optimal efficacy, with modest hematologic complete response (hCR) rates and often require prolonged treatment. Median event-free survival with second-line therapies is 14.3 months (Zanwar et al. Leukemia 2024). New therapies inducing deep and durable responses, including high hCR and minimal residual disease (MRD) negativity rates, are needed to avoid further treatment and extend survival. AZD0120 is an autologous CAR-T cell therapy targeting BCMA and CD19 currently being investigated for treating R/R multiple myeloma (MM) and early-line MM. Targeting both CD19 and BCMA in AL is anticipated to impact a wider range of clonal PCs and yield superior results vs single-target CAR-T cell products, as suggested in MM (Boucher et al. Clin Cancer Res 2012). Additionally, B cell lineage trees of clonal B cells and PCs from bone marrow of patients with AL show that CD19+ clonal B cells represent a clonal pre-PC precursor population (Manske et al. Clin Immunol 2006). Therefore, in AL, dual targeting may impact a wider range of clonal PCs and their progenitors, resulting in deep, durable responses. Efficacy was seen in investigator-initiated studies of AZD0120 in R/R and early-line MM (Du et al. JCO 2023; Du et al. Blood 2024, EHA 2024). ALACRITY aims to evaluate safety, efficacy, cellular kinetics and pharmacodynamics (PD) of AZD0120 in patients with R/R AL. Methods ALACRITY is a Phase 1b/2, open-label, multicenter, global, non-randomized study evaluating an i.v. dose of AZD0120 in patients with R/R AL; Phase 2 will expand. Participants must be ≥18 years old with histopathologically confirmed AL and current or historic organ involvement (e.g., cardiac, renal, hepatic, neurologic) per consensus criteria, measurable hematologic disease (difference between involved and uninvolved free light chains [dFLC] >20 mg/L or serum M-protein >5 g/L), and ECOG performance status 0–1. Participants must have relapsed or be refractory to ≥1 prior line of anti-PC-directed therapy, including a CD38 monoclonal antibody and a proteasome inhibitor. Key exclusion criteria include Mayo Stage IIIb cardiac involvement, systolic BP <100mmHg, symptomatic MM, oxygen saturation <95%, NYHA Class III–IV, active malignancy, extensive gastrointestinal involvement, and severe renal or hepatic dysfunction (e.g., creatinine clearance <30mL/min, AST/ALT >2.5×ULN), prior CAR-T or BCMA-directed therapy, or any FDA-approved or investigational T cell engaging therapy (e.g., bispecifics/trispecifics) at any target within the last 6 months. Multiple dose levels (DLs) of AZD0120 will be evaluated in Phase 1b. Any dose-limiting toxicity within the first 28 days following AZD0120 infusion will be evaluated. Any DLs deemed safe may enroll a maximum of 12 patients to evaluate safety, efficacy, cellular kinetics, and/or PD. The recommended Phase 2 dose (RP2D) will be selected based on safety, preliminary efficacy, cellular kinetics, and PD. Safety will be reviewed and characterized for all patients. Phase 2 will enroll ~79 patients at the RP2D. Study duration is 2 years after the last patient receives AZD0120, followed by long-term follow-up for a total of 15 years. The primary endpoint for Phase 2 is the proportion of patients achieving hCR. Secondary endpoints include overall response rate, duration of hematologic response, MRD negativity, overall survival, event-free survival, safety, and cellular kinetics. This study is registered on ClinicalTrials.gov (NCT07081646). Conclusion This study aims to determine the safety, tolerability, and efficacy of AZD0120 in adult participants with relapsed or refractory AL.

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