FDA’s Fast Track Designation Granted to Allogeneic CAR Therapy for B-cell Precursor Acute Lymphoblastic Leukemia

The FDA has granted a fast track designation to PBCAR0191, a CD19-directed allogeneic chimeric antigen receptor T-cell therapy, for the treatment of patients with advanced B-cell precursor acute lymphoblastic leukemia.

The FDA has granted a fast track designation to PBCAR0191, a CD19-directed allogeneic chimeric antigen receptor (CAR) T-cell therapy, for the treatment of patients with advanced B-cell precursor acute lymphoblastic leukemia (ALL).

“Fast Track Designation is intended to fill an unmet medical need by accelerating the development of agents for patients in need of potentially better therapeutic options,” said Chris Heery, MD, chief medical officer of developer Precision BioSciences, in a statement. “We continue to work toward demonstrating that PBCAR0191, as well as our other two allogeneic CAR T clinical programs, may play a role in the treatment paradigm of advanced malignancies in the future. We believe the balance of safety and efficacy plus the accessibility of allogeneic cell therapies may fill a void left by autologous CAR T therapies. This designation provides more flexibility as we attempt to identify the optimal patient population in which to seek regulatory approval.”

The investigational CAR T-cell therapy is currently being investigated in an ongoing multicenter, nonrandomized, open-label, parallel assignment phase 1/2a trial of adult patients with relapsed or refractory B-cell ALL and relapsed or refractory non-Hodgkin lymphoma (NHL) (NCT03666000).

In the study, lymphodepletion conditioning therapy of fludarabine and cyclophosphamide is given prior to infusion of PBCAR0191. Increasing doses from 3 x 105 cells/kg to 9 x 106 cells/kg will be assessed across 5 different dose levels. Higher doses will be given in multiple administrations.

Patients with B-cell ALL are eligible for the trial if they have relapsed/refractory CD19-positive disease and Philadelphia chromosome–positive disease is also allowed if the patient is intolerant to tyrosine kinase inhibition or has relapsed/refractory disease. In the NHL groups, eligible lymphomas include diffuse large B-cell lymphoma with or without Richter’s transformation, primary mediastinal B-cell lymphoma, follicular lymphoma including transformed follicular lymphoma, high-grade B-cell lymphoma, small lymphocytic leukemia (SLL), and mantle cell lymphoma (MCL). All patients must have received at least 2 prior chemotherapy-based treatment regimens, which must include ibrutinib (Imbruvica), idelalisib (Zydelig), and rituximab (Rituxan) in the case of SLL. Patients must also have CD19-positive disease; an ECOG performance status of 0 or 1; adequate bone marrow, renal, hepatic, pulmonary, and cardiac function; and be negative for HIV.

The trial includes both a dose-escalation and expansion phase to assess the safety and activity of PBCAR0191 and to determine the maximum tolerated dose of the CAR T-cell therapy. Secondary end points of the trial include objective response rate, duration of response, progression-free survival, overall survival, and time to next treatment.

All patients that receive treatment with PBCAR0191 will be followed in a separate long-term follow-up study for 15 years after the completion of this study.

According to early reports from the trial, which were presented at the 2019 American Society of Hematology Annual Meeting, no serious adverse events or cases of graft-versus-host disease were reported among the first 9 evaluable patients treated at the first 2 dose levels. Three of these patients developed cytokine release syndrome, which was grade 1 in 2 patients and grade 2 in 1. Grade 2 neurotoxicity was reported in 1 of the patients. All of these events resolved and no deaths have been reported yet on the study.2

A case of grade 3 treatment-related pain at the tumor site following infusion and grade 4 lymphopenia have been reported.

Seventy-eight percent of these patients, which included 6 with NHL and 3 with ALL, had tumor shrinkage. Of the 3 patients with ALL, 1 had a complete response at day 28+ and minimal residual disease negativity. The other 2 patients did not respond.

In the patients with NHL, there were 3 partial responses and 1 complete response. Only 1 of these patients remain in response.

According to an update from earlier this year, no dose-limiting toxicities or serious adverse events have been observed with the CAR T-cell therapy.3

After discussion with the FDA, Precision BioSciences made a protocol amendment to the ongoing trial to optimizing clinical activity by assessing higher total doses of cells and the impact of modified lymphodepletion regimens.

Interim clinical data from this study are expected to be presented from both the NHL and B-cell ALL cohorts later this year.

The FDA previously granted the CAR T-cell therapy an orphan drug designation for the treatment of patients with ALL and MCL.


1. Precision BioSciences Receives Fast Track Disease Designation from U.S. Food and Drug Administration for PBCAR0191 Investigational Allogeneic CAR T Cell Therapy. News release. Precision BioSciences. August 19, 2020. Accessed August 19, 2020. https://bit.ly/3l3igHp

2. Precision BioSciences Presents Updated Interim Clinical Data at the ASH Annual Meeting from Relapsed / Refractory NHL and B-ALL Patients Treated at Dose Levels 1 & 2 in the Ongoing Phase 1/2a Clinical Trial of PBCAR0191, a Novel CD19 Targeted Allogeneic CAR T Therapy Candidate. News release. Precision BioSciences. December 9, 2019. Accessed August 19, 2020. https://bit.ly/324Tzlr

3. Precision BioSciences Reports First Quarter 2020 Financial Results and Provides Business Update. News release. Precision BioSciences. May 15, 2020. Accessed August 19, 2020. https://bit.ly/3aE46Yy