The FDA has asked Juno Therapeutics to halt the phase 2 clinical trial
of JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (ALL), the ROCKET trial. The announcement came after Juno reported 2 additional deaths last week of patients enrolled in the trial, following the death of 1 patient back in May.
The culprit, according to the company, may be the drug fludarabine that was recently introduced in the preconditioning regimen, along with cyclophosphamide, and Juno has proposed to the FDA that they would continue the trial with the JCAR015 chimeric antigen receptor T (CAR-T) cells using cyclophosphamide alone for the preconditioning.
This setback follows encouraging results
that were presented by Cameron John Turtle, MBBS, PhD, Fred Hutchinson Cancer Research Center, at the annual meeting of the American Society of Clinical Oncology (ASCO) last month. According to Turtle, lymphodepletion using fludarabine improved both disease-free survival and overall survival in patients with relapsed/refractory ALL. While neurotoxicity and cytokine release syndrome were observed, he said they were manageable.
During a conference call today, Hans Bishop, president and chief executive officer of Juno Therapeutics Recent emphasized that the toxicities with fludarabine/cyclophosphamide (flu/cy) and JCAR015 need to be better understood. “We have seen encouraging safety and efficacy results with JCAR017 and JCAR014 in adult ALL, [chronic lymphocytic leukemia, CLL], and Non-Hodgkin lymphoma (NHL) patients, with as much as 70% complete response rate,” he said.
Mark Gilbert, MD, senior vice president and chief medical officer at Juno, reffered back to data presented at ASCO where 29% of pediatric and young adult ALL patients treated with JCAR017 had cytokine release syndrome (CRS) and neurotoxicity, and 39% of adult ALL patients developed CRS and neurotoxicity.
Bishop emphasized on the call that the complete response rate was 100% in adult, and pediatric and young adult ALL patients treated with JCAR017, and that there plans are on track for JCAR017. He said that the company expects approvals for JCAR017 in adult ALL, NHL, and CLL by the end of 2019.
“Although we have a setback in the ROCKET trial, with clinical hold, if FDA is satisfied with the data that we have submitted, and if the trial comes off hold, we can help meet a significant unmet need in these patients,” Bishop added.
In response to a question by an analyst on the call, Gilbert pointed out that the 3 patients who died were young, under 25 years of age, and that they are investigating why that may be. “Younger patients are usually more tolerant to neurotoxicity,” he said.
“We are recommending to the FDA that we use cyclophosphamide alone to reduce patient exposure. We anticipate that the FDA will review our submission in an expedited fashion, but it could take up to 30 days for them to make a decision.”
“Our plans remain unchanged. This safety signal may have to do with the combination of flu/cy with JCAR015,” Bishop said. He said that the company believes that preconditioning with cyclophosphamide alone could be the way to go to safely maintain patient benefit. “Whether flu/cy in JCAR015 will be used is yet to be determined by us internally,” he added.
The FDA, meanwhile, has requested that Juno submit a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation they made to the agency yesterday.