FDA Suspends UCART123 Trials After Patient Death

FDA Suspends UCART123 Trials After Patient Death

The U.S. Food and Drug Administration (FDA) has suspended two Phase 1 trials assessing Cellectis’ CAR T-cell therapy UCART123 in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) after the first patient died.

The clinical hold was prompted by the death in the BPDCN trial due to severe cytokine release syndrome (CRS), a common complication of immunotherapies, Cellectis announced in a press release.

Cellectis is now working with trial investigators and the FDA to try to resume studies with an amended protocol using a lower dose of UCART123.

UCART123 is a CAR T-cell therapy designed to target the CD123 molecule found at the surface of both AML and BPDCN cells. It uses immune T-cells harvested from unrelated donors that are engineered to specifically identify, bind, and kill CD123-positive cells.

The BPDCN trial, called ABC123 (NCT03203369), is being conducted at the MD Anderson Cancer Center. It started with the dosing of a 78-year-old male patient diagnosed with relapsed or refractory BPDCN. He presented skin lesions, and 30% of his bone marrow cells were malignant.

Prior to receiving the UCART123 cells, the patient was treated with fludarabine and cyclophosphamide, which prepares the patient to receive the treatment. Then, he received 625,000 UCART123 cells for each kilogram of his weight.

Five days after receiving the cells, the patient experienced moderate cytokine release syndrome — a common adverse reaction associated with an extreme response from the immune system — and a severe lung infection, which were reversed with the use of immunosuppressive therapy and broad spectrum antibiotics.

Three days later, the patient developed a lethal cytokine storm and life-threatening capillary leak syndrome, an event characterized by the escape of blood plasma from vessels to the surrounding tissues, causing blood pressure to drop. The patient was kept in immunosuppressive management and in intensive care.

Despite the efforts, the patient died nine days after initiating UCART123 therapy.

In the AML123 study (NCT03190278), conducted at Weill Cornell, the first patient to receive treatment was a 58-year-old woman with AML. The patient received the same preconditioning regimen and the same UCART123 dosage as in the ABC123 trial with no complications.

At day eight, the patient experienced moderate cytokine release syndrome, which progressed to a severe adverse effect the next day. Management therapy in an intensive care unit reversed this situation two days later. The patient also experienced life-threatening capillary leak syndrome that resolved by day 12.

After reviewing these serious treatment-related adverse effects, the trial’s Data Safety Monitoring Board (DSMB) recommended investigators lower the dose to 62,500 UCART123 cells per kg, and reduce the cyclophosphamide dose.

“We think there is a chance that CRS events could be mitigated upon lowering the dose of UCART123 beyond the DSMB recommendation and treating CRS symptoms more aggressively, although ultimately we look to more information,” Biren Amin, an analyst at Jefferies, wrote.

Cellectis is now attempting to resume the trials and to continue enrolling to reach the planned 72 BPDCN patients and 156 AML patients in each trial.