The FDA has lifted a clinical hold placed on a phase II study exploring the CD19-targeted CAR-T cell therapy JCAR015 for adult patients with relapsed or refractory B cell acute lymphoblastic leukemia.
The FDA has lifted a clinical hold placed just last week on a phase II study exploring the CD19-targeted CAR-T cell therapy JCAR015 for 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 trial was placed on hold to address 3 deaths from cerebral edema that occurred following the addition of fludarabine as part of a preconditioning regimen given prior to JCAR015. Under the new protocol design, which was accepted and approved by the FDA, preconditioning will consist of cyclophosphamide alone.
Two of the deaths that led to the 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. Typically, the FDA reviews clinical trial changes within 30 days.
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,1the 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.
"We remain encouraged by the ability of JCAR015 to treat ALL," said Hans Bishop, CEO at Juno Therapeutics. "The [ASCO] results show a marked improvement over traditional cytotoxic chemotherapy for adult ALL patients."
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).
"Although we have experienced a setback in the ROCKET trial with the clinical hold…we are optimistic that we will achieve results comparable to those in the phase I trial. These results should provide the basis for an accelerated approval," according to Bishop. "The early data with cyclophosphamide precondition alone in the ROCKET trial encourage us that using this approach will be comparable to the phase I experience.”
Fludarabine has a history of eliciting neurotoxicity, which dates back to the mid-1980's. In fact, investigation into fludarabine was nearly halted altogether for patients with leukemia, following the development of delayed central nervous system toxicity. Development was continued only after a maximum tolerated dose was found that compensated for fatal neurotoxicity.2,3
Given the currently available data, the added toxicity associated with fludarabine appears to be confined to trials exploring JCAR015, according to Bishop. Other trials utilizing the fludarabine/cyclophosphamide preconditioning regimen for Juno’s other CD19-directed CAR T-cell therapies, JCAR017 and JCAR014, will continue unchanged.
In non-Hodgkin lymphoma, a similar cyclophosphamide/fludarabine regimen is being utilized for studies of JCAR017 and JCAR014. For pediatric patients with ALL, a lower intensity dose of the preconditioning regimen is under exploration. This lower dose includes cyclophosphamide at 900 to 1000 mg/m2plus fludarabine at 25 to 30 mg/m2 over 3 days.
"Our JCAR017 plans remain on track. We expect to be able to have our first approval in the United States as early as 2018," Bishop said.