The FDA has placed a clinical hold 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 hold is meant to address 3 deaths that occurred in the trial from cerebral edema, which might be related to the recent addition of fludarabine to the preconditioning regimen used in the study. Two of the deaths occurred within the past week, leading to the halt. The first death was seen in May, although the cause of this event could not be determined.
In response to the hold, Juno plans to omit fludarabine from the trial, which is known as ROCKET, and will provide a complete response to the FDA this week. As part of the complete response, the FDA requested that Juno submit a revised patient informed consent form, investigator brochure, and trial protocol along with a copy of information presented to the agency. The FDA typically reviews this type of information submission within 30 days.
"The FDA placed the ROCKET trial on clinical hold after the occurrence of 2 deaths last week, which followed the addition of fludarabine to the preconditioning regimen on the trial," Hans Bishop, CEO at Juno Therapeutics, said during a webcast. "We have proposed to the FDA that we continue the trial using cyclophosphamide only preconditioning. In response, the FDA has asked us to submit 4 specific documents in complete response to the clinical hold. We will plan to submit them this week and the FDA has told us that they will review these documents on an expedited basis."
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.1,2
In a trial for patients with chronic lymphocytic leukemia from the mid-1990's, 14% of patients treated with fludarabine experienced neurotoxicity, which was primarily grade 1 motor dysfunction.3
Additionally, in 2011, an analysis of 1596 patients identified severe leukoencephalopathy in 2.4% of those treated with fludarabine prior to hematopoietic stem cell transplantation (HSCT).4
More recently, in a 2015 case report, a 55-year-old patient with myelofibrosis experienced severe, irreversible neurotoxicity following treatment with a fludarabine conditioning regimen and HSCT.5
The phase II ROCKET trial was designed to assess JCAR015 following lymphodepleting chemotherapy in 90 adult patients with ALL. The preconditioning regimen consisted of cyclophosphamide at 30 to 60 mg/kg plus 25 to 30 mg/m2
of fludarabine over 3 days.
The majority of patients treated in the trial received preconditioning with cyclophosphamide alone, according to Bishop. There have been no treatment related deaths in those receiving cyclophosphamide alone, and neurotoxicity is within the range of expectations, he noted.
"If the FDA is satisfied with the materials and lifts the clinical hold, we will continue the trial with the aim to make JCAR015 broadly available to adult patients with relapsed or refractory ALL," said 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; however, the hold will likely impact our ability to achieve our goal of getting JCAR015 approved as early as 2017."
Prior to this development, 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 CAR T-cell therapy.
In a phase I study that included 51 adult patients with ALL,6
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 this 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. The remaining 9 patients enroll 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.