July 12, 2016 – The American Food & Drug Administration (FDA) has notified Juno Therapeutics Inc. that a clinical hold has been placed on the Phase II clinical trial of JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL), known as the “ROCKET” trial. Details of the clinical trial with
JCAR015 can be found at clinicaltrials.gov here. The clinical hold follows after two patient deaths in the trial last week, and an apparent earlier death of another trial participant in May 2016. Based on the scarce information available to date, the deaths occurred after the recent addition of chemotherapeutic fludarabine to the pre-conditioning regimen associated with the intended therapy regimen.
JCAR015 are patient-derived T-cells genetically modified to express a chimeric antigen receptor (CAR) that will bind with high potency leukemia cells that express the CD19 protein on the cell surface (CD stands for Cluster of Differential (see here for more information). This is one possible concept in immunomodulation that is thought to help the patient’s own immune system to fight of and eliminate cancerous leukaemia cells.
The clinical trial with JCAR015 was aimed at determining if these modified T cells (JCAR015) in fact help the patients’s immune system to eliminate leukemia cells. Part of the tested treatment regimen was a lymphodepleting chemotherapeutic pre-treatment before JCAR015 infusion intended to deplete the patient’s natural repertoire of white blood cells which should be replaced by JCAR015 in order to populate the patient’s bloodstream. To reach that effect, researchers used fludarabine. Fludarabine in itself is a FDA-approved drug and is indicated for the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The tree patients who died in the present, now halted, clinical trial with JCAR015 had been pre-treated with fludarabine in preparation to the JCAR015-treatment. According to Juno Therapeutics Inc., the three patients died of cerebral edema, or swelling of the brain, and they were all in their early 20’s
Investigations into the deaths are ongoing; researchers believe that the addition of fludarabine to the treatment regimen may have produced a deadly treatment cocktail. It may be interesting to know in this context that the FDA’s drug label of Fludarabine lists cardiovascular edema as one of the very many serious adverse effects of this drug. Before resuming this trial, it remains to be understood i) if fludarabine in itself may also produce cerebral edema or brain swelling as one of the very many, sometimes serious or even fatal adverse effects, ii) if the combination of JCAR015 and fluradabine might increase the risk for these events, and iii) if there is a possibility that immunemodulatory interference on CD19 in itself may be involved in the etiology of cerebral edema through molecular mechanisms and/or interactions so far unknown or not yet appreciated. FDA will have to make sure, that such factors are fully assessed and taken into consideration before modified trial protocols could be accepted and a lift on the clinical hold on this trial be issued.