Phase 2
The first multicenter trial of a CAR T product was the Novartis-sponsored ENSIGN trial, which was conducted in the US [NCT02228096]. In the ENSIGN study, CTL019 was produced at the U Penn GMP facility, and GMP lentiviral vector was made at the CHOP vector core. This study developed the infrastructure to do multicenter CAR T cell therapy, including creating a logistics “cold chain” for shipping cryopreserved cells from and to the treating center. Subsequently, the FDA approval of tisagenlecleucel was based on results of the ELIANA study [NCT02435849], which was a single cohort, multicenter study to test the safety and efficacy of tisagenlecleucel for children and young adults with relapsed or refractory B-ALL. ELIANA was the first global CAR T cell study, enrolling patients at 25 centers in 11 countries, and was conducted in its entirety using cells manufactured in Novartis’s GMP facility, which is currently used for commercial manufacturing. In the primary analysis, 97 patients were enrolled, 79 were infused, and 18 were excluded due to tisagenlecleucel product-related issues, death, or other adverse events that precluded tisagenlecleucel infusion. The 79 patients who received tisagenlecleucel had undergone a median of 3 previous therapies and had a median bone marrow blast percentage of 74% at enrollment. A majority of them (61%) had previously undergone allogeneic HSCT. Lymphodepleting chemotherapy (moderate dose fludarabine and cyclophosphamide) was given prior to tisagenlecleucel infusion in 96% of patients; 3 patients did not receive lymphodepleting chemotherapy due to leukopenia. The overall response rate for patients who received tisagenlecleucel was 82% (95% CI 712-90) at 3 months, with the vast majority of the responders (98%) achieving a MRD negative state by multiparameter flow. For responders, RFS was 66% (95% CI 52-77) at 12 months and 62% (95% CI 47-75) at 24 months. In those patients who experienced a relapse, it was largely driven by CD19-negative escape variants. Eight patients underwent allogeneic HSCT while in tisagenlecleucel-induced remission, including 2 patients who were MRD+ and 2 patients with evidence of early B cell reconstitution21. Updated trial data presented at ASH in 2018 showed an OS among all infused patients of 76% (95% CI 63-86) at 12 months and of 66% (95% CI, 54-76) at 24 months 22.