The US Food and Drug Administration (FDA) has lifted the clinical hold due to a patient death on Phase I testing of UCART123 in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Cellectis S.A. (Paris, New York), the developer of a first-in-class gene-edited allogeneic CAR T-cell (UCART) therapy announced it has agreed with the agency to implement several revisions. The company said it is currently working with the investigators and clinical sites to obtain IRB‘s approval on the revised protocols and resume patient enrollment.
The clinical hold was put on the trials after a 78-year-old man with BPDCN died from cytokine release syndrome, a common side effect even of autologous CAR-T cell therapies that can be managed with Roche’s IL-6 receptor blocker tocilizumab, which had been approved recently for that purpose. However it was not clear, if this also applies to Cellectis off the shelf CAR-T cell therapy, which is expected to dramatically reduce the huge production cost of current CAR-T treatments when approved. Following the death and a worrysome CRS case in a 58-year-old woman with AML, the independent data monitoring committee recommended to lower the dose of UCART123 in both studies.
The FDA indicated that it will lift the clinical hold after implementation of the following revisions:
– Decrease of the cohort dose level to 6.25x104 UCART123 cells/kg;
– Decrease of the cyclophosphamide dose of the lympho-depleting regimen to 750 mg/m²/day over three days with a maximum daily dose of 1.33 grams of cyclophosphamide;
– Inclusion of specific inclusion criteria at Day 0, the day of UCART123 infusion, such as no new uncontrolled infection after receipt of lymphodepletion, afebrile, off all but replacement dose of corticosteroids, no organ dysfunction since eligibility screening;
– Provision to ensure that the next three patients to be treated in each protocol will be under the age of 65;
– Provision to ensure that the enrollment will be staggered across the UCART123 protocols AML123 and ABC123: at least 28 days should elapse between the enrollments of two patients across the two studies.
The news came on the heels of a huge month for the producers of autologous CAR-T cell therapies. Gilead Sciences acquired CAR-T developer Kite Pharma for US$12bn, which got the second FDA approval in October for the autologous CAR-T treatment Yescarta (axicabtagene ciloleucel), to treat adult patients with certain types of large B-cell lymphoma, including non-Hodgkin lymphoma. The first mover in the field, Swiss Novartis AG, had received the first ever approval in August to treat treatment-refractive B-cell precursor acute lymphoblastic leukemia (ALL) with Kymriah (tisagenlecleucel) in patients up to 25 years of age