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.