For a second time, a clinical hold has been placed on the phase II ROCKET study exploring the CD19-targeted CAR T-cell therapy JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (ALL), according to a statement from the developer of the immunotherapy, Juno Therapeutics.
The hold was voluntarily initiated by Juno after 2 patients experienced cerebral edema earlier this week. Both patients have died, according to Juno. The company is now in discussions with the FDA and the data safety monitoring board to assess its options with the JCAR015 program.
“We are faced with a difficult decision, considering the encouraging early efficacy data in this trial and the poor prognosis of these relapsed/refractory ALL patients, who have few, if any, treatment options. We hope to give you an update at our investor analyst presentation in the next few weeks,” Hans Bishop, CEO of Juno Therapeutics, said during a webcast today.
The FDA previously placed a clinical hold on the ROCKET study in July 2016 to address 3 deaths from cerebral edema that occurred following the addition of fludarabine as part of a preconditioning regimen given prior to JCAR015. The hold was lifted only 1 week after it was placed on the study, after Juno submitted and the FDA accepted a new protocol design in which preconditioning consisted of cyclophosphamide alone.
Two of the deaths that led to the initial study pause occurred in early July, which triggered the hold, with the first incidence noted in May, although the cause of this event could not be determined. Quickly following the hold, Juno submitted plans to omit fludarabine to the FDA, along with a revised patient informed consent form, investigator brochure, and trial protocol along with a copy of information presented to the agency.
Prior to the hold, JCAR015 had been granted an FDA breakthrough therapy designation for patients with relapsed or refractory B-cell ALL. This designation was based upon early findings showing a high complete response (CR) rate with the CD19-directed CAR T-cell therapy.
In a phase I study that included 51 adult patients with ALL, the CR rate with JCAR015 was 77% in those with morphologic disease (n = 31) and 90% in those with minimal disease (n = 20). At the time of the analysis, the median overall survival (OS) was not yet reached for those in the minimal disease arm. The median OS was 9 months for those with morphologic disease.
The first 42 patients enrolled in this study receive cyclophosphamide alone and the remaining 9 patients received both fludarabine and cyclophosphamide as preconditioning. Overall, severe cytokine release syndrome (sCRS) was observed in 27% of patients and grade 3 or higher neurotoxicity was observed in 29% of patients.
More patients in the morphologic disease cohort experienced CRS compared with those in the minimal disease group (42% vs 5%). When CRS did occur, 12 patients received tocilizumab, 11 received steroids, and 10 received both. Three patients with morphologic disease died due to toxicity versus none in the minimal disease cohort. Events leading to death consisted of sepsis/multi-organ failure (n = 2) and seizure with an unknown cause of death (n = 1).
In its statement, Juno noted that programs involving its other CD19-targeted CAR T-cell therapies, such as JCAR017, have not been impacted by the hold on the ROCKET trial.
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