FDA Grants RMAT Designation to ALLO-715 for Relapsed/Refractory Multiple Myeloma

The FDA granted a Regenerative Medicine Advanced Therapy (RMAT) designation to the allogeneic chimeric antigen receptor (CAR) T-cell therapy as a potential treatment for patients with relapsed/refractory multiple myeloma, according to Allogene Therapeutics, the developer of the off-the-shelf treatment.¹

“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 at Allogene Therapeutics. “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.”

RMAT designation is designed to accelerate the development and review processes for a variety of investigational agents, which includes the benefits of fast track and breakthrough designations. The FDA deems eligibility for RMAT designation for an investigational cell therapy if it is planned to treat, modify, reverse, or cure serious or life-threatening diseases. The treatment needs to also provide preliminary clinical data showcasing its potential to address unmet medical needs for that disease. Allogene Therapeutics also noted RMAT benefits include early discussions with FDA that could be focused on potential surrogate or intermediate end points, as well as methods that could meet post approval requirements.

The FDA granted the designation based on the potential of ALLO-715, which is aimed to target an unmet need for patients who have failed available treatments for multiple myeloma. ALLO-715 features a human-derived single-chain variable fragment anti-BCMA cell with a 4-1BB costimulatory domain.

Most recently, first-in-human findings of ALLO-715 from the ongoing phase 1 UNIVERSAL study (NCT04093596) were presented during the 2020 ASH Annual Meeting.²

UNIVERSAL is being conducted at 11 centers in the United States, and is recruiting patients with multiple myeloma who are refractory to their last treatment and who have received 3 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. An ECOG performance status score of 0 or 1 is required.

In the dose-escalation portion of the study, ALLO-715 is being evaluated as a single infusion across 4 doses: 40 x 106, 160 x 106, 320 x 106, or 480 x 106 CARs. Lymphodepletion regimens are comprised of fludarabine (F; 30 mg/m2 daily) plus cyclophosphamide (C; 300 mg/m2 daily) given on 3 days with the monoclonal antibody ALLO-647 (A; 13-30 mg x 3 days; FCA) or cyclophosphamide plus ALLO-647 (CA).

At the time of the 2020 ASH Annual Meeting presentation, 35 patients were enrolled. Four patients were ineligible due to organ failure from disease progression. Of the 31 patients who were in the safety population, the median age was 65 years (range, 46-76). Nearly half of the patients (48%) have high-risk cytogenetics and 23% had extramedullary disease. The efficacy population at data cutoff on October 30, 2020 included 26 patients across the 4 dosing levels, with a median follow-up of 3.2 months.

Results showed that, at the 320 x 106 CAR cells dose plus the ALLO-647 lymphodepletion regimen, the therapy elicited a 60% overall response rate (ORR; n = 6/10) responses, which included a very good partial-plus response (VGPR+) in 4 patients (40%).

Responses varied across the other dosing cohorts and lymphodepleting regimens. No responses were observed among 3 patients each who received CARs at 40 x 106 with FCA or 160 x 106 with CA, both with low-dose ALLO-647. The ORRs were 50% in 4 patients who received CARs at 160 x 106 with low–ALLO-647 FCA; 33% in 3 at 480 x 106 with low–ALLO-647 FCA; and 67% in 3 at 320 x 106 with low–ALLO-647 CA.

Regarding the safety population (n = 31), most adverse effects occurred at grades 1/2 severity, which included cytokine release syndrome (CRS) in 14 patients (45%) and infusion-related reactions to ALLO-647 in 7 (23%). Tocilizumab (Actemra) was used in 19% and steroids in 10% of these patients to manage CRS.

All-grade infections occurred in 13 patients (42%), including grade 3 events in 4 (13%). One patient (3%) died from a presumed fungal pneumonia related to progressive disease and the CA conditioning regimen but unrelated to ALLO-715. Neither neurotoxicity nor GVHD were reported.

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/3atevaM
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. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 129.