The FDA has placed a clinical hold on two gene-edited allogeneic CAR T-cell (UCART) phase 1 studies being conducted by Cellectis after the report of a patient death. The studies are evaluating UCART123 immunotherapy in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
The clinical hold was initiated after Cellectis reported one fatality in the BPDCN clinical trial. This was the first patient treated in the BPDCN study, a 78-year-old man treated with one prior therapy, who presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline prior to a conditioning regimen. He received 30 mg/m2 per day of fludarabine for four days and 1 g/m2 per day of cyclophosphamide for three days as a preconditioning regimen. On August 16, 2017 (day 0), the patient received 6.25 x 105 UCART123 cells per kilogram, the first dose level explored in the protocol, without complication. At day 5, the patient experienced grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which quickly improved after a first dose of tocilizumab (Actemra, Genentech) and the administration of broad-spectrum intravenous antibiotics. At day 8, the patient experienced grade 5 CRS, together with grade 4 capillary leak syndrome. Despite receiving treatment in keeping with CRS management, including the administration of corticosteroids and two doses of tociluzumab as well as intensive care unit support, the patient died on day 9.
The first patient treated in the AML study was a 58-year-old woman with 84% blasts in her bone marrow at baseline prior to a conditioning regimen. On June 27, 2017 (day 0), the patient received the same preconditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication. She experienced initial grade 2 CRS at day 8, worsening to grade 3 at day 9 and resolving at day 11 with treatment management in the intensive care unit. She also experienced grade 4 capillary leak syndrome at day 9, which resolved at day 12.
Neither patient experienced graft versus host disease.
The data safety monitoring board for the trials has recommended lowering the dose to 6.25 x 104 UCART123 cells per kilogram in both studies and capping cyclophosphamide to a total dose of 4 g over three days. Cellectis reports it is working closely with the investigators and the FDA in order to resume the trials with an amended protocol including a lowered dosing of UCART123.
Source: Cellectis; September 4, 2017.