Investigators will work with the FDA to assess the root cause of a grade 5 serious adverse effect in phase 2 PLAT-08 trial evaluating SC-DARIC33 in pediatric acute myeloid leukemia.
The FDA has placed a clinical hold on the phase 1 PLAT-08 trial (NCT05105152), evaluating SC-DARIC33 as a treatment for pediatric patients and young adults with relapsed/refractory acute myeloid leukemia (AML), due to a grade 5 serious adverse effect (SAE) that occurred on study, according to a press release from 2seventy bio, Inc.1
Developers previously announced that the PLAT-08 study was paused to internally investigate the reason for the reported SAE with their collaborators, the Seattle Children’s Hospital, in June 2023.2 Investigation into the potential pathobiology of this toxicity has led to several study protocol changes that developers believe may allow for the PLAT-08 study to continue.
Investigators will continue to work with the FDA to analyze why the toxicity occurred, and implement any proposed changes to the study protocol to allow the trial to continue as soon as possible, according to the press release.
“In June, we paused our PLAT-08 study in AML due to a grade 5 safety event and this has since been followed by a clinical hold by FDA,” Nick Leschly, chief kairos officer at 2seventy, said in the press release. “We’ve collaborated with Seattle Children’s to conduct a root-cause analysis and developed amendments to the protocol. Seattle Children’s will review these amendments with FDA with the goal of resuming the study as soon as possible.”
During an oral presentation at the 2023 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, investigators presented data on SC-DARIC33 from the PLAT-08 study.3 In one patient with extramedullary leukemia, investigators observed an expansion of SC-DARIC33 cells within an extramedullary leukemic infiltrate in the skin, thereby yielding hemorrhagic necrosis of the infiltrate. In a second patient, investigators observed expansion of SC-DARIC33 cells in the peripheral blood, which correlated with a significant transient reduction in CD33 leukemic burden in the blood.
“These data reinforce the potential of SC-DARIC333 as a new T-cell therapy approach in AML,” Steven Bernstein, MD, chief medical officer at 2seventy bio, said in a press release at the time these data were presented.
In the open-label, non-randomized phase 1 PLAT-08 study, pediatric and young adult patients with relapsed/refractory, CD33-positive leukemia with or without prior history of allogeneic hematopoietic cell transplantation received SC-DARICC33 followed by intermittent, orally administered rapamycin (Rapamune).
The study’s primary end points include AEs and the ability to successfully manufacture SC-DARIC33. The secondary end point is AML responses in those with relapsed/refractory CD33-positive leukemia.
Patients 30 years or younger with the ability to tolerate apheresis and a life expectancy of at least 8 weeks were eligible for enrollment on the trial. Additional inclusion criteria included having an appropriate stem cell donor source identified, a Lansky or Karnofsky performance status of at least 50, and adequate organ function.
Those with an active malignancy other than AML or a history of symptomatic non-AML central nervous system (CNS) or ongoing symptomatic CNS disease requiring medical intervention were not eligible to enroll on the trial. Having an active severe infection or primary immunodeficiency syndrome were also grounds for exclusion.