The formal hold comes approximately 2 months after Seattle Children’s paused the trial in accordance with the clinical study protocol stopping rules.
The FDA has placed a formal clinical hold on the phase 1 PLAT-08 clinical trial (NCT05105152) evaluating 2seventy bio’s SC-DARIC33, an investigational CD33-directed chimeric antigen receptor T-cell (CAR-T) therapy intended to treat acute myeloid leukemia (AML), in relation to the death of the first patient treated at the study’s second dose level (5x106 SC-DARIC33 T-cells/kg).1
The formal hold, communicated by e-mail on August 11, 2023, comes approximately 2 months after Seattle Children’s, which is collaborating with 2seventy on the development of SC-DARIC33, paused the trial in accordance with the clinical study protocol stopping rules and notified the FDA of the pause.1,2 2seventybio and Seattle Children’s, which have been investigating the root cause of the grade 5 serious adverse event leading to the death since the June 2023 pause, have identified several potential changes to the trial’s protocol that they anticipate could lessen the severity of the toxicity and enable resumption of trial activities. Both groups intend to discuss the root cause analysis and proposed protocol modifications with the FDA in planned future meetings with the goal of reinitiating PLAT-08 in as timely a manner as possible.
“It cannot be stated enough that the safety of every patient who participates in our studies or receives our therapies is of utmost priority to us and we continue to keep the patient’s family in our thoughts,” Steven Bernstein, MD, the chief medical officer of 2seventy bio, said in a conference call and live webcast.3 “...In collaboration with Seattle Children’s, both our partner and the regulatory study sponsor, we have been conducting a thorough investigation of the root cause of this event. This investigation has provided insights into the pathobiology of this toxicity leading to several study protocol changes which the team believes may mitigate this toxicity and allow for the continuation of the PLAT-08 study... We will continue to collaborate with Seattle Children’s and the FDA to determine appropriate next steps and a potential path forward here.”
SC-DARIC33 uses the company’s Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T-cell platform, which is intended to allow for regulation of CAR T-cell activity based on the presence of rapamycin.4 The first-in-human trial PLAT-08 is evaluating SC-DARIC33 in patients aged 30 years or younger whose disease is in its first early relapse, its first relapse refractory to reinduction therapy, or a second or later relapse.
“This past Friday, Seattle Children’s received the official notice of the FDA clinical hold,” Nick Leschly, the CEO of 2seventy bio, added on the conference call.3 “This was expected, and we need to hear more from the FDA in terms of [its] specific concerns and how it will impact the potential path forward for the program.”
Earlier this year, at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, 2seventy announced findings from 3 participants in PLAT-08 who received the study’s first dose level (1x106 SC-DARIC33 T-cells/kg).4 At a cutoff date of March 17, 2023, SC-DARIC33 infusions were noted to have been generally well-tolerated in the participants with no dose-limiting toxicities reported.
“Right now, we have done the root cause analysis; we’re confident that we have some proposals in collaboration with the FDA to get this study back up and rolling,” Leschly continued in response to a call-in question asking for more information about the analysis and future plans on the conference call. “We can’t get into the details of that right now because we want to make sure we honor the relationship, not only with the study and the patients, but also with the FDA, so that’s about as far as we can go at this point in time... It’s ongoing, we have a plan, it’s shared with Seattle Children’s, and the FDA engagement has begun. So, we’re confident, but we will share details at a subsequent date.”