Juno Therapeutics’ received notice of the hold on July 6, 2016 for its “ROCKET” trial in which more than 20 adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL) were enrolled.
According to the company, the two deaths followed the recent addition of fludarabine to the pre-conditioning regimen. A third patient previously died in May. All three suffered from cerebral edema - a swelling in the brain caused by excess fluid.
Dr. Stephan Grupp, Novotny Professor of Pediatrics, University of Pennsylvania Perelman School of Medicine, who is running a similar trial funded by Novartis that use CAR T cells to treat pediatric acute lymphoblastic leukemia patients, commented:
“We have not seen significant brain swelling in any of our pediatric acute lymphoblastic leukemia patients on the Children’s Hospital of Philadelphia/Penn study treated with CTL019 CAR-T cells. Most of these patients received fludarabine, the same chemotherapy drug added to the patients in the trial being conducted by Juno Therapeutics. Central nervous system related side effects have been seen in these patients, including confusion, aphasia and seizures in a small number of patients, but these effects have all resolved."
Grupp doesn't expect the Juno trial will affect similar CAR-T trials or the field as a whole; however he said there may be some discussion about fludarabine's role, "but this wouldn’t be a central issue,” he added.
Moving forward, Chris Williams, a Juno spokesperson told us, “We have proposed to the FDA that we continue the trial without fludarabine and are awaiting the agency’s response.”
Yesterday, Juno submitted a Complete Response to the Clinical Hold, which includes a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation made to the agency.
Williams added that “all other trials and programs are proceeding and are not affected by the hold on ROCKET.”
Juno previously reported that the CAR- T cell product candidate JCAR015 showed high response rates in adults with B-cell ALL.
The company also reported durable responses and survivals observed in subset of patients who do not go to transplant; comparable survival outcomes to transplant patients; and lower side effects in patients with minimal disease at the time of CAR T cell infusion. These results were presented earlier this year at ASCO 2016.
At the time, Mark J. Gilbert, M.D., Juno’s Chief Medical Officer commented, “The ongoing efficacy and duration of response for a large percentage of patients, specifically those who do not go on to stem cell transplant, continues to be impressive.”
“These findings provide us with further confidence about our development strategy and the ongoing Phase II ROCKET pivotal trial,” he added.
Tara Goodin, an FDA spokesperson, told us that “The FDA cannot confirm or deny the existence of or comment on any current or pending investigational new drug (IND) applications.”
However, she explained that in general, when serious adverse events – such as death – occur in a clinical study under an FDA IND, a “clinical hold” is placed while the FDA works with the company “to evaluate the situation in order to help assure the safety of human subjects participating in the trial.”
“Cellular therapies, including Chimeric Antigen Receptor (CAR) T-Cell therapies, hold great promise in the treatment of serious and life-threatening diseases,” said Goodin. “We therefore do everything possible to assist sponsors in advancing clinical development programs in an effort to bring promising therapies to patients.”
Yet she added that the FDA recognizes the potential risks that investigation products intended to treat serious disease pose to patients as well.
Goodin said, “To this end, the FDA constantly looks at the risk-benefit profile of experimental therapies and when we have concerns about the risks, we may place the clinical trials on hold.”
“The agency will continue to work with sponsors to ensure patients and investigators participating in CAR-T cell clinical studies are fully informed regarding the risks and potential benefits of these experimental therapies,” added Goodin.