FDA Lifts Clinical Hold on BCMA-Directed Modified CAR T-Cell Therapy in Multiple Myeloma

The FDA has lifted the partial clinical hold placed on the clinical program evaluating the investigational new drug, CART-ddBCMA, in the treatment of patients with relapsed/refractory multiple myeloma.¹

In June 2023, the FDA placed a partial clinical hold on the phase 2 iMMagine-1 trial (NCT05396885) following the death of a patient.² At that time, Arcellx, Inc., the drug developer, posited that limitations on bridging therapy may have been a contributing factor to the patient’s death, although a reason for death was not stated.

In the announcement issued on August 15, 2023, the company stated that the death involved a patient who was treated with CART-ddBCMA despite becoming ineligible for treatment under the trial protocol prior to infusion with the product. They also noted that subsequently, the patient was managed in a way that conflicted with the study protocol.¹

The clinical hold was lifted after Arcellx and the FDA aligned on modifications to the trial protocol related to the prevention and management of adverse effects (AEs). The regulatory agency also permitted an expansion of bridging therapy options that patients enrolled in the iMMagine-1 trial could receive to better align the protocol with current clinical practice.

“We have worked closely with [the] FDA to expeditiously resolve the clinical hold and we thank them for their collaboration and dialogue throughout this process,” Rami Elghandour, chairman and chief executive officer of Arcellx, stated in a news release. “During the review process, we updated our trial protocol, and were pleased that [the] FDA allowed for expanded bridging therapies, which better aligns our protocol with current clinical practice. As a key step to enhancing protocol adherence related to the prevention and management of the risk of AEs, we retrained clinical sites.”

During the partial clinical hold, the FDA approved dosing of all 17 patients who had been enrolled, but not yet dosed prior to the hold, according to Elghandour added; this minimized treatment disruption.

In data from a phase 1 trial (NCT04155749) presented at the 2022 ASCO Annual Meeting, patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy or were triple-class refractory who were treated with either 100 x 106 CAR T cells or 300 x 106 CAR T cells (n = 31) experienced an overall response rate (ORR) of 100%, including a complete response (CR) or stringent CR (sCR) rate of 71% and a very good partial response (VGPR) or better rate of 94%.³

The dose-expansion portion of the study resulted in the selection of 100 x 106 CAR T cells as the recommended phase 2 dose (RP2D).

Regarding safety, grade 1/2 cytokine release syndrome (CRS) was reported in 88% of patients treated at the RP2D (n = 25); however, no grade 3 or higher CRS was observed in this group. In patients treated at 300 x 106 CAR T cells (n = 6), 83% experienced a grade 1/2 CRS event, and 17% had grade 3 CRS. The rates of grade 1/2 and grade 3 immune effector cell–associated neurotoxicity in the cohort that received 100 x 106CAR T cells were 20% and 4%, respectively. In the cohort that received 300 x 106 CAR T cells, those rates were 0% and 17%, respectively.

iMMagine-1 is an open-label, single-arm, phase 2 study evaluating CART-ddBCMA in patients at least 18 years of age with relapsed/refractory multiple myeloma who have received at least 3 systemic regimens including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, and are refractory to the last line of therapy.⁴ Patients are also required to have an ECOG performance status of 0 or 1, a life expectancy of more than 12 weeks, and adequate organ function.

Key exclusion criteria include plasma cell leukemia or history of plasma cell leukemia; solitary plasmacytomas without evidence of other measurable disease; severe or uncontrolled intercurrent illness or laboratory abnormalities; or active central nervous system involvement.

Following apheresis, enrolled patients are being treated with lymphodepletion followed by a single dose of CART-ddBCMA at 115 ± 10 x 106 CAR T cells. Bridging therapy is permitted during the manufacturing of the CAR T-cell therapy.

ORR is serving as the trial’s primary end point. Secondary end points include sCR/CR rate, ORR in patients limited the 3 prior lines of therapy, duration of response, VGPR/PR rate, time to initial response, progression-free survival, overall survival, pharmacokinetics, anti–CART-ddBCMA antibodies, and health-related quality of life.

“We and our partners at Kite remain confident in CART-ddBCMA’s potential as a best-in-class therapy for the treatment of patients with relapsed/refractory multiple myeloma given the totality of data to date across our studies. We have a strong balance sheet funding operations through biologics license application filing and into 2026,” Elghandour added. “We look forward to presenting data from our phase 1 study later this year as well as preliminary data from the iMMagine-1 study in the second half of 2024. Additionally, we continue to expect commercial launch of CART-ddBCMA to be in 2026.”

References

1. Arcellx announces partial clinical hold lifted on IMMagine-1 phase 2 clinical program and reports second quarter financial results. News release. Arcellx. August 14, 2023. Accessed August 15, 2023. https://ir.arcellx.com/news/news-details/2023/Arcellx-Announces-Partial-Clinical-Hold-Lifted-on-iMMagine-1
2. Arcellx announces clinical hold for its IMMagine-1 phase 2 clinical program. News release. Arcellx, Inc. June 19, 2023. Accessed August 15, 2023. https://ir.arcellx.com/news/news-details/2023/Arcellx-Announces-Clinical-Hold-for-its-iMMagine-1-Phase-2-Clinical-Program/default.aspx
3. Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. J Clin Oncol. 2022;40(suppl 16):8003. doi:10.1200/JCO.2022.40.16_suppl.8003
4. Study of CART-ddBMCA in relapsed or refractory multiple myeloma (iMMagine-1). ClinicalTrials.gov. Updated March 22, 2023. Accessed August 15, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05396885