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Update: The hold on this trial has been lifted. Click here for additional details.
A trial of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 has been placed on clinical hold following 3 patient deaths.
The trial, known as ROCKET, is a phase 2 study of adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
The US Food and Drug Administration (FDA) placed a hold on the trial after 3 patients died of cerebral edema.
All 3 patients had received conditioning with fludarabine, and Juno Therapeutics, the company developing JCAR015, believes this may have caused the patients’ deaths.
Patients enrolled on the ROCKET trial previously received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy.
The addition of fludarabine to conditioning had been shown to increase the efficacy of 2 of Juno’s other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.
“However, since adding fludarabine to the preconditioning on the ROCKET trial, we have seen an increase in the incidence of severe neurotoxicity, which has, unfortunately, included 2 patient deaths that occurred last week from cerebral edema that appeared to be treatment-related,” Hans Bishop, Juno’s president and chief executive officer, said in a conference call.
“After the first of these 2 deaths, we immediately paused the trial for an internal review and review with our Data Safety Monitoring Board [DSMB] and the FDA. There was also 1 previous death from cerebral edema on the trial in May. After a review of that event, we, along with the FDA and our DSMB, concluded there were confounding factors, and a change in our plans at the time was not warranted.”
After the more recent deaths, Juno investigated several factors that could have contributed, including the conditioning regimen, patient characteristics, toxicity management, product characteristics, and cell dose.
“Although more than 1 factor may have contributed, based on our review of the data available . . . , we believe the addition of fludarabine, when combined with JCAR015, is the most likely and the most appropriately modifiable factor,” Bishop said.
“Indeed, with cy[clophosphamide] 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, and the incidence of severe neurotoxicity is within the range of what we expected in light of the Memorial Sloan-Kettering experience [phase 1 trial of JCAR015].”
Therefore, Juno has proposed continuing the ROCKET trial using conditioning with cyclophosphamide alone.
In response to this request, the FDA has requested that Juno submit:
- A revised patient informed consent form
- A revised investigator brochure
- A revised trial protocol
- A copy of a presentation the company made to the FDA.
The FDA said it will expedite the review of these documents and expects to complete the review within 30 days of receiving them.
If the clinical hold on the ROCKET trial is lifted, Juno plans to continue the trial. However, the hold will likely impact the company’s goal of gaining FDA approval for JCAR015 in 2017.
Juno’s trials and plans for its other CD19-directed CAR-T cell product candidates are not affected by the clinical hold placed on ROCKET.
ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical 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.
