The Food and Drug Administration has given the biopharmaceutical company Cellectis permission to resume phase 1 trials of UCART123, a gene-edited T-cell investigational drug that targets CD123, as a potential treatment for acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to a press release from the company.

UCART123 is the first allogeneic, “off-the-shelf” gene-edited chimeric antigen receptor (CAR) T-cell product candidate that the FDA has approved for clinical trials. The agency had placed a clinical hold on phase 1 trials of the gene-edited CAR T-cell drug on Sept. 4, following a patient death in the BPDCN clinical study. In order to proceed with the trials, Cellectis agreed to several changes in the study protocols.

The changes include decreasing the dose of the UCART123 therapy to 6.25×104 cells/kg and lowering the dose of the lympho-depleting regimen of cyclophosphamide to 750 mg/m2 per day over 3 days with a maximum daily dose of 1.33 g. Additionally, there can be no uncontrolled infection after receipt of the lympho-depleting preconditioning regimen. Patients must be afebrile at the start of treatment, off all but a replacement dose of corticosteroids, and have no organ dysfunction. Plus, the next three patients treated in each study must be under age 65.

There’s also a condition that patient enrollments be staggered by at least 28 days.

The drug sponsor is working with investigators and each clinical site to obtain the Institutional Review Board’s approval of the revised protocols.

The hold followed the death of a 78-year-old man with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions. The first dose of UCART123 at 6.25×105 cells/kg was administered without complication, but at day 5 the patient began experiencing side effects, including cytokine release syndrome and a lung infection. At day 8, the cytokine release syndrome had worsened and the patient had also developed capillary leak syndrome. He died on day 9 of the study.

In the AML phase 1 study , a 58-year-old woman with AML and 84% blasts in her bone marrow received the same dose of UCART123. She also developed cytokine release syndrome and capillary leak syndrome but both resolved with treatment.

Both patients also received the same preconditioning treatment: 30 mg/m2 per day fludarabine for 4 days and 1g/m2 per day cyclophosphamide for 3 days.

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