FDA Grants RMAT Designation to Novel Allogeneic CAR T-Cell Agent in Relapsed/Refractory Multiple Myeloma

The FDA has granted a regenerative medicine advanced therapy (RMAT) designation to the allogeneic chimeric antigen receptor (CAR) T-cell therapy ALLO-715 for the treatment of patients with relapsed or refractory multiple myeloma, according to a press release from Allogene Therapeutics, Inc.¹

ALLO-715 has the potential to address an expanding unmet medical need for patients with multiple myeloma who have failed on other therapies. Treatment with ALLO-715 in this patient population is currently being evaluated in the phase 1 UNIVERSAL study (NCT04093596).

“RMAT designation was granted based on our encouraging initial clinical experience in heavily pretreated patients. ALLO-715 demonstrated for the first time that an allogeneic CAR T therapy directed at BCMA can achieve deep clinical responses while eliminating the need for bridging therapy and delays associated with autologous CAR T manufacturing,” said Rafael Amado, MD, executive vice president of research and development and chief medical officer. “We look forward to completing the UNIVERSAL study and working closely with the FDA as we seek to rapidly advance this important therapeutic alternative to patients with advanced multiple myeloma.”

Nineteen patients with multiple myeloma were enrolled in the study and 15 were dosed with the CAR T-cell agent at 4 different dose levels including, 40 x 10⁶, 160 x 10⁶, 320 x 10⁶, and 480 x 10⁶ CAR+ T cells, according to a 3 + 3 dose-escalation design. The primary end point of the study is the occurrence of dose-limiting toxicities (DLTs) and safety/tolerability. As secondary end points, the study is evaluating anti-tumor activity and pharmacokinetics.²

The population assessed was heavily pretreated with a median of 5 prior lines of therapy (range, 3-11), and 31.6% of patients had stage 3 disease. All but 1 of the patients included in the study previously underwent autologous stem cell transplant (ASCT), 52.6% had high-risk cytogenetics, and 26.3% had extramedullary disease.

In patients who received 320 x 10⁶ CAR T cells, activity was seen in 3 out 5 patients. The objective response rate in these patients was 60% (95% CI, 14.7%-94.7%). In addition, a complete response and very good partial response (VGPR) was observed in 1 patients each. Local minimal residual disease testing of the patients showed that those with at least a VGPR had minimal residual disease negative status. Notably, 80% of patients with a response were still responding to ALLO-715 at the time of data cutoff. The findings suggested that a higher dose of CAR T cells leads to anti-cancer activity in patients with relapsed/refractory multiple myeloma.

In terms of safety, the most common grade ≥3 adverse events (AEs) observed were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). There was also 4 episodes of grade ≥3 infections in 4 separate patients. Another patient had a grade 5 infection. There was also 1 death in the study due to respiratory failure.

No dose-limiting toxicities occurred with ALLO-715 treatment, and 24% experienced cytokine release syndrome.

The study of ALLO-715 in relapsed/refractory multiple myeloma is a first-in-human study designed with the intention of addressing the challenges with and availability of CAR T-cell therapy for these patients. The agent is a genetically modified anti-BCMA allogeneic CAR T-cell product, which has been preclinically shown to reduce the development of graft-versus-host disease TCR alpha constant gene disruption.

The UNIVERSAL study is actively recruiting up to 90 patients who have measurable disease, received at least 3 prior line of therapy, have an ECOG performance status of 0 or 1, and have adequate hematologic, renal, hepatic, pulmonary, and cardiac function. The study excludes individuals who have current or history of central nervous system (CNS) involvement, clinically significant CNS disorder, a current or historic thyroid disorder, ASCT within the last 6 weeks, received prior treatment with anti-BCMA therapy, any gene therapy, any genetically modified cell therapy, or adoptive T cell therapy, have a history of HIV infection or acute or chronic active hepatitis B or C infection, and those who refuse to participate in an extended safety monitoring period.

With an RMAT designation, the development of ALLO-715 for the treatment of relapsed/refractory multiple myeloma may be expedited as will review process with the FDA. Expedited review by the regulatory body will include fast track and breakthrough therapy designation.¹

_References:

_{1. Allogene Therapeutics announces FDA regenerative medicine advanced therapy (RMAT) designation granted to ALLO-715, an AlloCAR T™ cell therapy in development for relapsed/refractory multiple myeloma. News release. Allogene Therapeutics. April 21, 2021. Accessed April 21, 2021. https://bit.ly/3xgeuAA}

_{2. Mailankody S, Matous JV, Liedtke M, et al. Universal: An allogeneic first-in-human study of the anti-BCMA ALLO-715 and the anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Blood. 2020;136(suppl 1):24-25. doi: 10.1182/blood-2020-140641}