After chromosomal abnormality was detected in a single patient treated on the ALPHA 2 trial, the FDA placed a clinical hold on the study pending further information.
The FDA placed a clinical hold on the ALPHA2 trial (NCT04416984) on ALLO-501A CAR T-cells after a case of chromosomal abnormality was reported in a single patient, according to the agent’s developer Allogene Therapeutics, Inc.
The trial is examining ALLO-501A, an allogeneic CD19-targeting CAR T-cell product, plus ALLO-647 and lymphodepleting chemotherapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) who have not previously received autologous CAR T-cell therapy.
“Patient safety is our highest priority, and we are committed to working closely with the FDA to evaluate any potential clinical implications of this finding and determine next steps for advancing ALLO-501A and our clinical programs,” Rafael Amado, MD, Executive Vice President of Research and Development and Chief Medical Officer of Allogene Therapeutics, Inc, said in a statement. “As a leading developer of allogeneic cell therapies, we recognize our added responsibility to fully assess all aspects of our therapies to advance the field. We are grateful for the partnership with the patient community, clinical investigators, our Scientific Advisory Board, and the FDA as we work diligently toward understanding the clinical significance of this finding and to support the development of allogeneic CAR T therapy for cancer.”
The hold was placed after a chromosomal abnormality in a bone marrow biopsy was reported in 1 patient with stage IV transformed follicular lymphoma and c-myc rearrangement who was sampled to assess pancytopenia. Of note, the patient was previously treated with 2 prior lines of immuno-chemotherapy and additional radiation therapy and was unable to receive autologous CD19-targeting CAR T-cell therapy following a manufacturing error that led to inadequate cell expansion.
Following CAR T-cell infusion, the patient developed grade 1 cytokine release syndrome and grade 2 immune effector cell-associated neurotoxicity syndrome requiring high-dose steroids. Progression to pancytopenia led to discovery of the chromosomal abnormality. Early data showed peak CAR T-cell expansion on day 28. Initially, the patient had a partial response to ALLO-501A and then underwent allogeneic stem cell transplantation.
Further investigation is underway to determine the clinical relevance of this event, evidence of clonal expansion, or potential relationship to gene editing. The FDA continues to evaluate end of phase 1 materials submitted in expectation of a pivotal phase 2 trial for ALLO-501A.
In data reported at the 2021 American Society for Clinical Oncology, encouraging clinical activity was noted in a small group of patients (n = 9) treated on the trial. The objective response rate (ORR) was 56% (95% CI, 21%-86%) and a 44% (95% CI, 14%-79%) complete response rate was reported.
In those who received ALLO-501A at the second dose level of 120 × 106 CAR T-cells (n = 4), the ORR was 50% (95% CI, 7%-93%), which included 2 complete responses. For those who received ALLO-501A as a consolidation treatment (n = 5), the ORR was 60% (95% CI, 15%-95%) and the complete response rate was 40% (95% CI, 5%-85%).
In the study, non-human leukocyte antigen–matched patients with disease across a range of lymphomas including relapsed/refractory LBCL, DLBCL, transformed follicular lymphoma, transformed marginal zone lymphoma (MZL), primary mediastinal B-cell lymphoma (PMBCL), and grade 3B follicular lymphoma were treated with ALLO-501A.
The primary end point of the trial is safety, tolerability, and cell kinetics of ALLO-501A following lymphodepletion. Secondary end points are investigator-assessed ORR, as well as cell kinetics of ALLO-501A.