Juno Therapeutics ($JUNO) had hoped to have a first approval for one of its candidates next year. But that looks unlikely to happen as the pivotal trial for this lead candidate has been put on hold by the FDA after three patient deaths.
The FDA initiated the clinical hold on the Phase II clinical trial of JCAR015, known as ROCKET, which is in adult relapsed or refractory B cell acute lymphoblastic leukemia. The move was made after two patient deaths last week that appear to be treatment-related. There was also an earlier death in the study, but the FDA had determined that due to confounding factors a change in the trial wasn’t warranted at that time.
All three deaths were in young patients, all under the age of 25, and all were due to cerebral edema. All three of these patients were also on a preconditioning regimen of fludarabine.
Juno said it suspects that it’s this fludarabine preconditioning regimen that’s the problem and has proposed to the FDA that it continue the ROCKET trial using JCAR015 with cyclophosphamide preconditioning only. The company started the trial using cyclophosphamide alone, but it then added fludarabine.
"Since adding fludarabine to the preconditioning on the ROCKET trail we have seen an increase in the incidences of severe neurotoxicity which was unfortunately included, two patients deaths have occurred last week from cerebral edema that appeared to be treatment related," said Juno CEO Hans Bishop on a July 7 conference call.
He added, "After the first of these deaths, we immediately pulled the trial for an internal review and review with our Data Safety Monitoring Board and the FDA. There was also one previous death from cerebral edema on the trial in May. After review of that event, we, along with the FDA and our DSMB, concluded there were confounding factors and that a change in our plans at the time was not warranted."
The FDA said it will need Juno to submit four documents: a revised patient informed consent form, a revised investigator brochure, a revised trial protocol and a copy of the presentation to the agency.
The company said the FDA will expedite its review, which is expected to take 30 days at most. That’s after Juno submits these documents, which it is slated to do next week.
Most troubling is the extent to which this could be an early indication of a safety issue for the entire class of chimeric antigen receptor T cell (CAR-T) treatments. Juno said that the FDA may go on to investigate this question.
"I obviously can't speak for the FDA formally, they have put together a voluntary participation database of the experience with CAR-T cells and looking at different toxicities. So, I could imagine that they may investigate this," responded Bishop when queried specifically on if FDA might conduct a class-wide investigation.
The company did say that the deaths in these cases may be related to a very rapid expansion of the cells in the patients’ bodies that it hasn’t seen in other trials or with other preconditioning regimens. Juno’s CAR-T technology takes the patient’s own T cells and genetically engineers them to recognize and combat cancer cells. It is used in combination with standard chemotherapy that includes fludarabine and cyclophosphamide.
Juno said it plans to continue with trials for other CD19-directed CAR-T product candidates, including JCAR017. It continues to expect it’s on track for an approval in 2018 for JCAR017 but declined to update the time line for JCAR015. Juno said it would detail its plans for the troubled candidate at its next earnings call in August.
In aftermarket trading on July 7, Juno dropped by more than 25% on news of the trial halt.
- here is the release
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