CAR-T CELL TRIAL ON HOLD

The US Food and Drug Administration (FDA) has put the brakes on a mid-stage clinical trial of an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy after two patients died, Juno Therapeutics, Inc, announced July 7.

The CAR T-cell approach, which involves taking T-cells from patients, engineering them, and then reinfusing them back into the patient, has produced dramatic results in clinical trials in leukemia and lymphoma patients, as previously reported by Medscape Medical News.

The trial that has been put on hold is known as the JCAR015 phase 2 ROCKET trial, which is being conducted in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The two deaths in the trial occurred following the addition of fludarabine to the preconditioning regimen.

When the ROCKET trial began, preconditioning consisted of cyclophosphamide only, Hans Bishop, Juno's chief executive officer, said in a teleconference. Later in the trial, fludarabine was added to the preconditioning regimen. The switch to the two drugs "was attractive in light of improved efficacies shown from data in multiple trials, notably the JCAR14 phase 1/2 trial in advanced B-cell malignancies and the JCAR17 phase 1/2 trial in pediatric ALL," Bishop explained.

"However, since adding fludarabine to the preconditioning on the ROCKET trial, we have seen an increase in the incidence of severe neurotoxicity, which unfortunately included two patient deaths that occurred last week from cerebral edema that appeared to be treatment-related," Bishop said.

"After the first of these two deaths, we immediately called the trial for internal review and review with our data safety monitoring board (DSMB) and the FDA," he noted. There was also one previous death from cerebral edema on the trial in May. However, after review of that event, the company, along with the FDA and the DSMB, concluded that a change in trial protocol was not warranted at that time, Bishop said.

Bishop said that after reviewing multiple factors that could have contributed to the increased neurotoxicity seen in the ROCKET trial, "we believe the addition of fludarabine when combined with JCAR15 is the most likely and the most appropriately modifiable factor. Indeed, with cyclophosphamide alone, which we have used in the greatest number of patients treated in the ROCKET trial to date, there have not been any treatment-related deaths."

The company has proposed that the ROCKET trial be continued using JCAR015 with cyclophosphamide preconditioning alone. The FDA has asked Juno to submit four documents as a response to the clinical hold: a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation the company made to the FDA on July 7. Juno said it will submit the requested documents by the end of this week, and the FDA is expected to review it on an expedited basis.

The company said its other CAR T-cell therapy trials have not been affected by the clinical hold that has been placed on the ROCKET trial.