FDA Places Clinical Hold on Select Allogeneic CAR T Trials After Report of Chromosomal Abnormality

The FDA

The FDA has placed a hold on clinical trials examining Allogene Therapeutics, Inc.’s allogeneic CAR T-cell therapies for patients with cancer, following a report of a chromosomal abnormality in ALLO-501A CAR T cells in a patient who received treatment in the phase 1/2 ALPHA2 study (NCT04416984).¹

The abnormality was identified in a bone marrow biopsy that was done to evaluate pancytopenia. Efforts are being made to further characterize the abnormality to gain a better understanding on clinical relevance, evidence of clonal expansion, or its potential relationship to gene editing.

The patient in whom the abnormality was detected had stage IV transformed follicular lymphoma (FL) with c-myc rearrangement, and their disease was refractory to 2 prior lines of chemoimmunotherapy and additional radiation therapy. The patient was not able to receive an autologous CD19-targeted CAR T-cell therapy because of a manufacturing failure linked with inadequate expansion of autologous CAR T cells.

After receiving ALLO-501A, the patient reported grade 1 cytokine release syndrome (CRS) and grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS). To manage these effects, the patient was given high-dose steroid therapy. The patient went on to develop progressive pancytopenia. Upon bone marrow biopsy, the patient demonstrated aplastic anemia and the presence of ALLO-501A CAR T cells with a chromosomal abnormality.

Earlier translational data indicated the expansion of the CAR T cells, with a peak at day 28, and contraction thereafter. The patient achieved a partial response to the CAR T-cell product and then underwent allogeneic stem cell transplantation (ASCT). Prolonged cytopenia requiring rescue SCT has previously been reported with these autologous therapies.

“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., stated in a press release.

To overcome logistical and manufacturing challenges associated with autologous CAR T-cell therapies, investigators have turned to the development of allogeneic products.² The anti-CD19 CAR T-cell therapy ALLO-501 has rituximab (Rituxan) recognition domains and data with the product supported the development of ALLO-501A, which does not include those domains.

ALLO-501A is an allogeneic, anti-CD19 CAR T-cell product that utilizes TALEN gene editing to disrupt the TCRα constant gene, which could reduce the risk of graft-versus-host disease. The edited CD52 gene could also allow for the use of ALLO-647 to selectively deplete host T cells.

The phase 1 ALPHA trial (NCT03939026) enrolled 42 patients with relapsed or refractory large B-cell lymphoma (LBCL) or FL who had previously received 2 or more lines of therapy. Forty-one of these patients received treatment with ALLO-501; of these patients, 21 had FL and 20 and LBCL. Notably, 9 of the patients had previously received autologous CAR T-cell therapies.

Data showed that in all evaluable patients (n = 32), the CAR T-cell product elicited an objective response rate (ORR) of 75% (95% CI, 57%-89%), with a complete response (CR) rate of 47% (95% CI, 29%-65%). In the subset of those with FL (n = 21), the ORR with the product was 81% (95% CI, 58%-95%); this rate was 64% (95% CI, 31%-89%) in the subset of those with LBCL (n = 11).

Utilizing what was learned with ALPHA, ALPHA2 was launched as a single-arm, open-label trial that would examine ALLO-501A in non-human leukocyte antigen–matched patients with relapsed or refractory LBCL, which could include diffuse large B-cell lymphoma, transformed FL, transformed marginal zone lymphoma, primary mediastinal large B-cell lymphoma, or grade 3B FL.

To be eligible for enrollment, patients must have previously received at least 2 lines of therapy, which included an anthracycline and an anti-CD20 monoclonal antibody. Retreatment was permitted for those who experienced disease progression or stable disease with suboptimal CAR T expansion.

The protocol was recently amended so that patients who achieved disease stability or better at day 28 could receive consolidation therapy with an additional 30-mg dose of ALLO-647 and ALLO-501A infusion.

The primary end points of the trial include safety, tolerability, and cell kinetics of the product following lymphodepletion, and key secondary end points comprise investigator-assessed ORR and cell kinetics of ALLO-501A.

The mean age for all 13 patients enrolled to the trial was 55 years, 39% had stage IV disease, 69% had an ECOG performance status of 1, 69% had a baseline lactate dehydrogenase level greater than the upper limit of normal, and the mean number of prior regimens received was 3. Moreover, 31% of patients previously received an anti-CD19 treatment, 54% had a germinal center disease subtype, and 46% had double- or triple-hit disease.

Data presented during the 2021 ASCO Annual Meeting showed that ALLO-501A elicited an ORR of 56% (95% CI, 21%-86%) in 9 evaluable patients, with a CR rate of 44% (95% CI, 14%-79%). Notably, the benefit of consolidation dosing was indicated in 3 of 3 patients who had a scan following their second dose.

Regarding safety, no patients had reported dose-limiting toxicities (DLTs). In the consolidation arm, which comprised 6 patients, a second dose of ALLO-647 and cell infusion had been planned for administration. No CRS, ICANS, DLTs, dose reductions, or related severe adverse effects occurred. The more frequent toxicities experienced with the product included neutropenia, leukopenia, lymphopenia, thrombocytopenia, and anemia.

“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,” Amado added. “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.”

Allogene Therapeutics, Inc. will provide more updates in the coming weeks after a consultation is held with the regulatory agency. The FDA will continue to actively review the end-of-phase-1 materials that were submitted in anticipation of a potential phase 2 trial examining the product.

References

1. Allogene Therapeutics reports FDA clinical hold of AlloCAR T trials based on a single patient case in ALPHA2 trial. News release. Allogene Therapeutics, Inc. October 7, 2021. Accessed October 7, 2021.https://bit.ly/3AjVj9j
2. Locke FL, Malik S, Tees MT, et al. First-in-human data of ALLO-501A, an allogeneic chimeric antigen receptor (CAR) T-cell therapy and ALLO-647 in relapsed/refractory large B-cell lymphoma (R/R LBCL): ALPHA2 study. J Clin Oncol. 2021;39(suppl 15):2529. doi:10.1200/JCO.2021.39.15_suppl.2529