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The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.
The ROCKET trial was placed on hold after 3 patients died of cerebral edema.
Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.
In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.
The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.
ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
