FDA Grants CAR T-cell Therapy ALLO-715 Orphan Drug Status for Multiple Myeloma

The FDA has granted an orphan drug designation to the allogeneic CAR T-cell therapy ALLO-715 for the treatment of patients with multiple myeloma, according to an announcement from Allogene Therapeutics, Inc., the drug developer.¹

Data from the ongoing phase 1 UNIVERSAL trial (NCT04093596) demonstrated that when the therapy was administered at the 320 x 106 CAR cells dose plus an ALLO-647 lymphodepletion regimen, it elicited an overall response rate (ORR) of 60% among 10 patients; this included a very good partial response or better in 40% of patients.²

In April 2021, the regulatory agency had granted ALLO-715 a Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of patients with relapsed/refractory multiple myeloma.³ RMAT designation is designed to accelerate the development and review processes for investigational products. If an agent is planned to treat, modify, reverse, or cure serious or life-threatening diseases, it is eligible for RMAT designation.

“We are pleased to have received orphan drug designation for ALLO-715 just months after the FDA granted RMAT designation. These designations from the FDA underscore the importance of bringing this important therapeutic option to patients with multiple myeloma,” Rafael Amado, MD, executive vice president of Research & Development and chief medical officer at Allogene, stated in a press release. “We look forward to presenting the next update from our UNIVERSAL trial by the end of 2021 and providing additional insight into the potential of our allogeneic cell therapy.”

ALLO-715 targets BCMA and is under development for multiple myeloma and other BCMA-positive malignancies.

UNIVERSAL, which is being conducted at 11 centers throughout the United States, is recruiting patients with multiple myeloma who are refractory to their last treatment and who have previously received 3 or more therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. To be eligible for enrollment, patients need to have an ECOG performance status of 0 or 1.

In the dose-escalation portion of the trial, the therapy was examined via a single infusion across the following 4 doses: 40 x 10⁶, 160 x 10⁶, 320 x 10⁶, or 480 x 10⁶ CARs. The lymphodepletion regimens are composed of fludarabine (F) at a daily dose of 30 mg/m² plus cyclophosphamide (C) at a daily dose of 300 mg/m² given for 3 days with ALLO-647 (A; FCA) at doses ranging from 13 mg to 30 mg every 3 days or cyclophosphamide plus ALLO-647 (CA).

At a data cutoff of October 30, 2020, 26 patients were included in the efficacy population of the trial across the 4 dosing levels. Responses were varied across the dosing cohorts and lymphodepleting regimens used. Specifically, no responses were observed among those who received CARs at 40 x 10⁶ with FCA (n = 3) or 160 x 10⁶ with CA (n = 3), both with low-dose ALLO-647.

In the 4 patients who received CARs at 160 x 10⁶ with low–ALLO-647, the ORR was 50%. In 3 patients who were given CARs at 480 x 10⁶ with low–ALLO-647 FCA, the ORR was 33%; this rate was 67% in 3 patients who were administered CARs at 320 x 10⁶ with low–ALLO0647 CA.

A total of 35 patients had been enrolled to the trial but 4 patients were determined to be ineligible because of organ failure from progressive disease. Among the 31 total patients included in the safety population, the median age was 65 years (range, 46-76). Of these patients, 48% had high-risk cytogenetics and 23% had extramedullary disease.

Most of the toxicities that were reported with the therapy were grades 1 or 2; these effects included cytokine release syndrome (45%) and infusion-associated reactions to ALLO-647 (23%). To manage the CRS, tocilizumab (Actemra) was given to 19% of patients and 10% received steroids.

All-grade infections were experienced by 42% of patients, with 13% experiencing grade 3 effects. Three percent of patients died from a presumed fungal pneumonia associated with progressive disease and the CA conditioning regimen but unrelated to the CAR T-cell therapy. Notably, neurotoxicity and graft-versus-host disease were not experienced.

References

1. Allogene Therapeutics receives FDA orphan drug designation (ODD) for ALLO-715 for the treatment of multiple myeloma (MM). News release. Allogene Therapeutics, Inc. August 12, 2021. Accessed August 16, 2021. https://bit.ly/3yYxsw8
2. 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 August 16, 2021. https://bit.ly/3atevaM
3. 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