FDA Places Clinical Hold on Phase 1 Trial of SC-DARIC33 in Pediatric R/R CD33+ AML

The FDA has placed a clinical hold on the phase 1 PLAT-08 trial (NCT05105152) evaluating SC-DARIC33 in pediatric and young-adult patients with relapsed/refractory CD33-positive acute myeloid leukemia (AML).¹

In June 2023, the trial was paused following the report of a fatal, grade 5 serious adverse effect (SAE) in a patient being treated with the investigational CD33-targeted CAR T-cell therapy, leading to an internal investigation and root cause analysis by 2seventy bio and Seattle Children’s Hospital.^1,2

“This investigation provided insights into the potential pathobiology of this toxicity which led to several study protocol changes, which the team believes may mitigate this toxicity and allow for the continuation of the PLAT-08 study,” 2seventy bio wrote in an announcement of the clinical hold.¹ “2seventy bio and Seattle Children’s will continue to work with FDA to provide the root cause analysis and proposed changes for the clinical study. Based on upcoming discussions with FDA, 2seventy bio and Seattle Children’s plan to amend the study accordingly and resume this study as soon as possible.”

SC-DARIC33 uses 2seventy bio’s proprietary dimerizing agent regulated immunoreceptor complex (DARIC) T-cell platform.³ In previously reported data from PLAT-08, 3 patients were treated at dose level 1 of SC-DARIC33 at 1 x 106 T cells/kg following lymphodepletion chemotherapy. SC-DARIC33 was generally well tolerated, and no dose-limiting toxicities were reported.

The first-in-human, non-randomized, open-label, dose-finding PLAT-08 study was enrolling patients 30 years of age or younger with AML. Patients were 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. Confirmed CD33 expression by flow cytometry, a Lansky performance status of at least 50, a life expectancy of at least 8 weeks, and an identified donor for stem cell transplant were also required for inclusion.⁴

Patients were excluded if they had 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 were undergoing lymphodepletion with fludarabine and cyclophosphamide prior to SC-DARIC33, followed by rapamycin to activate the CAR T-cell therapy.³

The co-primary end points were AEs associated with SC-DARIC33 infusions and the ability to manufacture the CAR T-cell therapy. AML response was a key secondary end point.⁴

References

1. 2seventy bio reports second quarter financial results and recent operational progress. News release. 2seventy bio. August 14, 2023. Accessed August 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-reports-second-quarter-financial-results-and-0
2. 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 August 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-announces-clinical-study-pause-plat-08-trial-sc
3. 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 August 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-presents-late-breaking-results-sc-daric33
4. 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 29, 2023. Accessed August 14, 2023. https://clinicaltrials.gov/ct2/show/NCT05105152