Phase 1 Trial of SC-DARIC33 in Pediatric R/R CD33+ AML on Hold After Serious Grade 5 AE

Steve Bernstein, MD

The phase 1 PLAT-08 trial (NCT05105152) investigating SC-DARIC33 in pediatric and young-adult patients with relapsed/refractory CD33-positive acute myeloid leukemia (AML) has been paused following the report of a grade 5 serious adverse effect (AE), according to an announcement from 2seventy bio.¹

The pause was initiated by Seattle Children’s Hospital, which is the regulatory sponsor of the study. The FDA has been notified of the fatal AE, and the cause of the grade 5 event and its potential association with SC-DARIC33 are currently under investigation.

“Importantly, I’d like to offer that our thoughts are with the family during this time. The safety of every patient who participates in our studies or is treated with our therapies is the utmost priority for us, and we are in communication with FDA while we assess the data surrounding this serious AE, and the potential next steps for the study,” Steve Bernstein, MD, chief medical officer of 2seventy bio, stated in a news release.

SC-DARIC33 is an investigational CD33-targeted CAR T-cell therapy that uses 2seventy bio’s proprietary dimerizing agent regulated immunoreceptor complex (DARIC) T-cell platform.² Previously reported data from PLAT-08 showed that 3 patients received SC-DARIC33 at dose level 1 of 1 x 106 T cells/kg following lymphodepletion chemotherapy, and the infusions of the CAR T-cell therapy were generally well tolerated with no dose-limiting toxicities reported.

PLAT-08 is a first-in-human, non-randomized, open-label, dose-finding phase 1 study enrolling patients 30 years of age or younger with AML. Patients are required to be in first relapse within 6 months of diagnosis, first relapse after 6 months of diagnosis refractory to reinduction, or in second relapse or beyond. Other key inclusion criteria include confirmed CD33 expression by flow cytometry, a life expectancy of at least 8 weeks, and an identified donor for stem cell transplant.³ Patients under 16 years of age need a Lansky performance status of at least 50, and those at least 16 years of age are required to have a Karnofsky score of at least 50.

Key exclusion criteria include an active malignancy other than AML; a history of symptomatic non-AML central nervous system (CNS) disease or ongoing symptomatic CNS disease; symptomatic CNS AML involvement; active graft-vs-host disease in patients who have a history of allogeneic stem cell transplant; or primary immunodeficiency syndrome.

Enrolled patients are treated with lymphodepletion consisting of fludarabine and cyclophosphamide before receiving SC-DARIC33, followed by rapamycin to activate the CAR T-cell therapy.²

The co-primary end points include AEs associated with SC-DARIC33 infusions and the ability to manufacture the CAR T-cell therapy. AML response is a key secondary end point.³

References

1. 2seventy bio announces clinical study pause of PLAT-08 trial of SC-DARIC33 in acute myeloid leukemia. News release. 2seventy bio. June 14, 2023. Accessed June 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-announces-clinical-study-pause-plat-08-trial-sc
2. 2seventy bio presents late-breaking results for SC-DARIC33, an investigational CD33-targeting CAR T in pediatric and young adults with relapsed or refractory acute myeloid leukemia. News release. 2seventy bio. May 19, 2023. Accessed June 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-presents-late-breaking-results-sc-daric33
3. PLAT-08: A study of SC-DARIC33 CAR T cells in pediatric and young adults with relapsed or refractory CD33+ AML. ClinicalTrials.gov. Updated June 12, 2023. Accessed June 14, 2023. https://clinicaltrials.gov/ct2/show/NCT05105152