Results from the phase I ZUMA-1 study into KTE-C19 CAR T-cell therapy in refractory DLBCL

This month in Molecular Therapy, Frederick L. Locke from the Moffitt Cancer Centre, Tampa, Florida, and Sattva S. Neelapu from the University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues reported the phase I results of the multicenter ZUMA-1 trial into KTE-C19 anti-CD19 CAR T-cell treatment in refractory DLBCL patients. Patients with refractory DLBCL traditionally have very few treatment options remaining and poor prognosis and overall survival rates (CR 8%, median OS 6.6 months¹). The authors here report the results of the first multicenter phase I study of anti-CD19 CAR T-cell therapy in this population². The CAR construct used in this study was manufactured in a centralized process and functioned as a proof-of-concept for this kind of delivery of patient-specific CAR T-cells.

Key Highlights:

• Protocol:
  • Conditioning regimen of cyclophosphamide (500mg/m²) and fludarabine (30mg/m²) on days -5, -4, and -3
  • Target dose: 2x10⁶ KTE-C19 CAR T-cell/kg at day 0
• 9 pts enrolled, 7 received KTE-C19, 2 discontinued due to disease progression
• All patients were refractory to at least 2 treatments, four post-ASCT
• ORR = 71%, within 1 month of receiving KTE-C19
• CR = 57%
• After 12 months three patients (42%) have ongoing CR having previously relapsed after ASCT within 6 months
• Adverse Events
  • Cytokine Release Syndrome (CRS) reported in 86% pts
  • 14% pts had grade 4 CRS, 71% pts had <grade 3 CRS
  • Median time to CRS was 1 day, median duration of CRS was 7 days
  • Neurotoxicity experienced at least once in all pts (7), 43% (3) grade 3, 14% (1) grade 4
  • CRS and neurotoxicity was reversible and self-limiting in all but one patient (who had dose-limiting toxicity)
• KTE-C19 manufacturing was successful for all pts

The authors concluded that the protocol in this study was effective and safe for further study, due to manageable toxicity, and proved the feasibility of this method of manufacturing and distributing CAR T-cell therapies. Furthermore, the authors used cryopreserved KTE-C19, and the successful expansion shown in this study (7–14 days) and subsequent high patient CR rate indicate that cryopreservation is feasible. In summary, KTE-C19 treatment was shown to be effective for multiple-refractory DLBCL patients, with a tolerable safety profile suitable for further study. The results from this study went on to inform the ongoing ZUMA-1 phase II trial, the first results from which we reported on last month after they were presented at the American Society of Hematology annual meeting.

Abstract:

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days followed by KTE-C19 at a target dose of 2 × 10⁶ CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.