Cellectis acknowledged that the FDA has placed on clinical hold its two Phase I studies of UCART123 following the death of a patient in the trial assessing the gene-edited allogeneic chimeric antigen receptor T-cell (CAR-T) immunotherapy candidate in blastic plasmacytoid dendritic cell neoplasm (BPDCN).
The clinical hold applies to the BPDCN trial as well as to a trial assessing UCART123 in acute myeloid leukemia (AML).
The patient who died was a 78-year-old man treated with one prior therapy, who showed relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) before undergoing treatment, Cellectis said.
According to Cellectis, the patient received a preconditioning regimen consisting of 30 mg/m2 per day fludarabine for 4 days and 1 g/m2 per day cyclophosphamide for 3 days. On August 16, he received 6.25×105 UCART123 cells per kilogram, the first dose level explored in the protocol, without complication.
Five days later, the patient experienced a grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which quickly improved after a first dose of tocilizumab and institution of broad-spectrum intravenous antibiotics. Eight days following treatment, Cellectis said, the patient experienced a grade 5 CRS, together with a grade 4 capillary leak syndrome.
“Despite a treatment in keeping with CRS management including administration of corticosteroids and tociluzumab x 2 as well as intensive care unit support, the patient died on day 9,” Cellectis said yesterday in a statement.
Reduced Dosing Planned
Cellectis said it is working closely with investigators and the FDA to resume the trials with an amended protocol that will include a reduced dosing of UCART123. The company cited a recommendation of the trials’ Data Safety Monitoring Board, which on August 28 advised Cellectis to lower its dose to 6.25×104 UCART123 cells per kilogram in both studies and cap cyclophosphamide to a total dose of 4 g over 3 days.
Cellectis also disclosed an adverse event related to the first patient treated in the AML study. She is a 58-year-old woman, with 84% blasts in her bone marrow before initiating the conditioning regimen in advance of treatment.
On June 27, the company said, the patient received the same preconditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication. She experienced an initial grade 2 CRS eight days following treatment. The CRS worsened to grade 3 the following day, but was resolved on day 11 with treatment management in intensive care unit.
The female AML patient also experienced a grade 4 capillary leak syndrome nine days after treatment, a condition that was resolved on day 12, Cellectis added.
The company added that none of the two patients were reported to have graft-versus-host disease.
Shares of Cellectis fell nearly 23% in morning trading from Friday’s closing price of $32.18, to $24.71 as of 10:03 a.m.
Cellectis is not alone in reporting deaths tied to CAR-T therapies. In March, Juno Therapeutics halted development of JCAR015, its lead CAR-T candidate indicated for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), four months after a second clinical hold was placed on a Phase II trial in which five patients died from cerebral edema.
Kite Pharma in May acknowledged the death of a patient in a trial of its CAR-T treatment axicabtagene ciloleucel (formerly KTE-C19) for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) in patients who are ineligible for autologous stem cell transplant. The patient died due to cerebral edema following multiple organ failure—though Kite added that it was the only such case of 300-plus patients treated with the therapy, and that the patient showed rapidly progressing refractory NHL before being dosed.
Kite—which has agreed to be acquired by Gilead Sciences for $11.9 billion, in a deal announced August 28—is awaiting an FDA decision on its Biologics License Application for axicabtagene ciloleucel, for which the agency has set a target action date of November 29, 2017 under the Prescription Drug User Fee Act (PDUFA).