Phase 1 Clinical Results of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®

Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) (Kochenderfer et al. Blood 2012, J Clin Onc 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). The ZUMA-1 trial is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Preliminary phase 1 results presented.

Methods: Subjects received KTE-C19 at a target dose of 2 x 10⁶ (minimum 1 x 10⁶) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 is to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Cytokine release syndrome (CRS) was graded per revised criteria (Lee et al. Blood 2014). Key secondary objectives include evaluating the overall response rate (ORR=CR+PR) per Cheson 2007, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as stable disease or progressive disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Subjects must have received at least prior anti-CD20 therapy and an anthracycline containing regimen.

Results: As of 28 July 2015, 6 subjects were dosed in the phase 1 portion of the study. All subjects are evaluable for safety with a median follow up time of 4.8 weeks post KTE-C19 infusion and 3 subjects have had 1 month tumor assessments. Two subjects experienced only grade (gr) 1-2 KTE-C19 related events. Three subjects had gr 3 KTE-C19 related events as highest gr toxicities; all these events were reversible within 3 days. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. One subject experienced a DLT of gr 4 encephalopathy and gr 4 CRS. This subject died within 30 days of KTE-C19 cell infusion; the death was due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Of the 3 subjects assessed for response at one month, 2 achieved a complete response and one achieved a partial response. Key safety and efficacy findings are summarized in the table. Biomarker and translational endpoints are included in a separate abstract. Enrollment is ongoing and updated trial results will be presented.

Conclusions: Preliminary phase I results ofthe ZUMA-1 study demonstrate that KTE-C19 can be centrally manufactured and administered in a multicenter trial. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease at 1 month after KTE-C19 administration. This potentially pivotal study is the first enrolling multicenter anti-CD19 CAR T cell trial in refractory aggressive NHL. Clinical trial: NCT02348216.

mo - months

M - male, F - female

N/A - not applicable