Zuma‐23: a Global, Phase 3, Randomized Controlled Study of Axicabtagene Ciloleucel Versus Standard of Care as First‐line Therapy in Patients With High‐risk Large B‐cell Lymphoma
Year: 2023
Type: article
Study design: Study Protocol
Abstract: Introduction: The nearly 40% of patients with large B-cell lymphoma (LBCL) who are refractory to or relapse after current first-line standard-of-care (SOC) regimens, such as R-CHOP (rituximab [R] + cyclophosphamide [C], doxorubicin [H], vincristine [O], and prednisone [P]) and DA-EPOCH-R (dose-adjusted etoposide [DA-E]), have poor prognoses. High International Prognostic Index (IPI) score and the subtype of high-grade B-cell lymphoma (HGBL) are associated with shorter progression-free and overall survival (PFS and OS; Nastoupil LJ and Bartlett NL. J Clin Oncol. 2023). Strategies to improve outcomes in these subgroups have been largely unsuccessful; therefore, therapeutic options with a different mechanism of action are needed.Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved to treat patients with relapsed/refractory LBCL after demonstrating significant clinical benefit as second line (ZUMA-7; Locke FL, et al. N Engl J Med. 2022) and third line and above (ZUMA-1; Neelapu SS, et al. N Engl J Med. 2017) therapy. Additionally, in the Phase 2 ZUMA-12 study in patients with refractory first-line LBCL, axi-cel showed a high rate of durable responses with an objective response rate of 89% (complete response rate, 78%) and an ongoing response rate of 73% (median follow-up, 15.9 months; Neelapu SS, et al. Nat Med. 2022). ZUMA-23 is the first Phase 3, randomized controlled study to evaluate CAR T-cell therapy as a first-line regimen for any cancer and will assess axi-cel versus SOC in patients with high-risk LBCL, defined as IPI 4–5.Methods: The Phase 3 trial design will enroll ≈300 adult patients with high-risk, histologically confirmed LBCL based on the 2016 WHO classification, including diffuse large B-cell lymphoma, HGBL, and transformed follicular or marginal zone lymphoma (Swerdlow SH, et al. Blood. 2016). Eligible patients will receive 1 cycle of R-chemotherapy and then be randomized 1:1 to receive axi-cel or continue with SOC. Patients in the axi-cel arm will undergo leukapheresis and then receive R-CHOP or DA-EPOCH-R as bridging therapy, followed by lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×106 CAR T cells/kg). Prophylactic corticosteroids may be administered to reduce the incidence and severity of cytokine release syndrome at the investigator’s discretion. Patients in the SOC arm will receive 5 additional cycles of R-CHOP or DA-EPOCH-R (investigator’s choice).The primary endpoint is event-free survival by blinded central review. Key secondary endpoints are OS and PFS. Safety, quality of life, and pharmacokinetics will also be assessed. Patients with a history of HIV and/or hepatitis B or C and undetectable viral loads may enroll. Key exclusion criteria include LBCL of the central nervous system. ZUMA-23 is open for enrollment (NCT05605899).
Source: Hematological Oncology
DOI: 10.1002/hon.3163_t06
Institutions: The University of Texas MD Anderson Cancer Center, Dana-Farber Cancer Institute, Moffitt Cancer Center, Institut Català d'Oncologia, Université de Lille, Centre Hospitalier Universitaire de Lille, Helios Hospital Berlin-Buch, The Royal Melbourne Hospital, The University of Melbourne, Peter MacCallum Cancer Centre, Cancer Research UK, NIHR CRUK Experimental Cancer Medicine Centre, University of Southampton, Sarah Cannon, Fred Hutch Cancer Center, Amsterdam University Medical Centers, Colorado Blood Cancer Institute, Kite (United States)
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4379981785