Juno Therapeutics has halted development of JCAR015, its lead chimeric antigen receptor (CAR) T-cell cancer immunotherapy indicated for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), nearly 4 months after placing a Phase II trial of the candidate on its second clinical hold following two additional patient deaths.
The deaths brought to five the number of patients who died from cerebral edema in the Phase II ROCKET trial of JCAR015.
“We have 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,” Juno president and CEO Hans Bishop said yesterday in a statement.
He said Juno plans to share detailed data from the ROCKET trial at an unspecified upcoming scientific conference.
“We remain committed to developing better treatments for patients battling ALL and believe an approach using our defined cell technology is the best platform to pursue,” Bishop added.
To that end, he said, Juno intends next year to launch a trial with a defined cell product candidate in adult ALL.
Juno didn’t say what that candidate will be. The company’s CAR T-cell cancer immunotherapy furthest in development at present is JCAR017. In December, Juno presented positive preliminary data on JCAR017 in patients with r/r aggressive non-Hodgkin lymphoma (NHL), reporting an 80% overall response rate and a 60% complete response rate.
“Looking forward into 2017, we continue to be optimistic about the progress we are making with JCAR017 and our pipeline more broadly,” Bishop said.
JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the co-stimulatory signaling domain to mimic a “second signal” that amplifies the activation of CAR T cells, which according to Juno leads to a more robust signal to the T cell to multiply and kill the cancer cell.
Juno reasons that candidates with a defined cell composition, such as JCAR017, will avoid the patient safety problems experienced by the CD19-directed JCAR015.
“We continue to experience encouraging signs of clinical benefit in our trial addressing NHL, but we also recognize the unfortunate and unexpected toxicity we saw in our trial addressing ALL with JCAR015,” Bishop stated.
In the ROCKET trial assessing JACR015, the first clinical hold imposed in July followed the deaths of three patients, which the company blamed on a change to the trial’s original protocol to precondition patients by using a combination of cyclophosphamide and fludarabine.
But the two most recent deaths leading to the second clinical hold occurred in November after resumption of the original cyclophosphamide-only protocol, which occurred when the ROCKET trial was resumed just 2 weeks after the first hold was imposed.
Since the second halt, Juno said, it has investigated the patient deaths, concluding that the tragic results reflected “patient-specific factors, the conditioning chemotherapy patients received, and factors related to the product.”
Juno said protocol modifications and process improvements could enable the company to resume clinical testing of JCAR015 in adult r/r ALL—but only after a Phase I trial establishing preliminary safety and dose.
“As a result of the timing delay that would entail and Juno’s belief that it has other product candidates in its pipeline that are likely to provide improved efficacy and tolerability, Juno, in collaboration with partner Celgene, has made a strategic decision to cease development of JCAR015 at this time and to redirect associated resources to the development of a defined cell product candidate in the adult r/r ALL setting,” Juno added.
JCAR015 is among CAR T-cell candidates covered by Juno’s 10-year, approximately $1 billion global collaboration launched in 2015 to develop and commercialize cancer and autoimmune diseases immunotherapies.
Juno's setbacks contrast with the biologics license application planned this year by Novartis, and the rolling BLA in progress by Kite Pharma—which on Tuesday reported positive 6-month trial data for its CAR T-cell lead candidate.