Juno Therapeutics has conceded defeat on lead CAR-T therapy JCAR015, terminating its trial in leukaemia patients after five deaths.
The decision was widely expected as the ROCKET trial in relapsed or refractory B cell acute lymphoblastic leukaemia (ALL) patients had already been placed on a clinical hold twice during 2016 after deaths resulting from cerebral oedema, or swelling in the brain.
After the first deaths were reported Juno indicated the problem lay with a fludarabine-containing pre-conditioning regimen used to prepare patients for the CAR-T procedure, which involves an infusion of modified CAR-T cells that have been engineered to attack tumour cells.
Last July the company got a green light to restart the trial with a different pre-conditioning regimen, but additional deaths in November resulted in the FDA imposing another clinical hold. Fludarabine is still being used in pre-conditioning regimens developed by other companies, and it appears that some other factor caused toxicity in the JCAR015 trial.
For now Juno is still unclear about what those may be, alluding to “patient specific factors, the conditioning chemotherapy patients received, and factors related to the product” in a statement.
On a conference call, CEO Hans Bishop said it appears that aggressive pre-conditioning therapy resulted in “rapid early CAR-T cell expansion in the patient” and that this “correlates with the risk of severe CRS [cytokine release syndrome], severe neurotoxicity and cerebral oedema”.
The company added that after discussions with its partner Celgene it had “decided not to move forward with the ROCKET trial or JCAR015 at this time, even though it generated important learnings for us and the immunotherapy field”.
Lowering the intensity of the conditioning chemotherapy by removing fludarabine in the second phase of the ROCKET trial did low the risk, but did not eliminate it, he added.
Now, Juno is pinning its hopes on a new candidate for non-Hodgkin lymphoma (NHL) called JCAR017 that the company believes will offer improved safety and efficacy, but will not be ready to start phase I clinical trials of that CAR-T until next year. The setback puts it far behind its rivals in the CAR-T space – headed by Kite Pharma and Novartis – which could both be filed for approval this year.
This week Kite reported results from a phase II trial of its KTE-C19 in patients with aggressive NHL, showing the therapy had sustained efficacy over six months and allaying concerns that early responses to the therapy could tail off.