The FDA has put a phase 1 trial of Cellectis off-the-shelf CAR-T therapy UCARTCS1A on clinical hold after learning of a death in the study. Cellectis said the multiple myeloma patient suffered a cardiac arrest after receiving the highest dose of the anti-CS1 allogeneic CAR-T.

Before joining the Cellectis trial, the patient underwent multiple prior lines of treatment, including with autologous CAR-T cells, without success. In the Cellectis trial, the patient was the first person to receive the higher, 3 million cells per kilogram dose of UCARTCS1A. The patient experienced cytokine release syndrome of undisclosed severity and died of a cardiac arrest 25 days after treatment.

The FDA has placed the trial on clinical hold while Cellectis evaluates the case. According to Cellectis, plans were already afoot to expand the lower, 1 million cells per kilogram dose cohort before the patient death. Preliminary data suggest 1 million cells per kilogram may be the phase 2 dose.

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There are signs the lower dose also has some safety issues. Analysts at Jefferies think investigators gave one or more of the three low-dose patients rituximab to activate the CAR-T safety switch. Work is underway to update the phase 1 protocol to mitigate the potential risks posed by UCARTCS1A.

The modifications may include increased monitoring of parameters related to cytokines. The Jefferies analysts think Cellectis should exclude patients previously treated with anti-BCMA CAR-Ts, such as Johnson & Johnsons JNJ-4528, due to risks related to back-to-back rounds of lymphodepletion, but note that management at the biotech think it is important to enroll that pre-treated population.

In a follow-up note, the analysts identified the use of cyclophosphamide, a chemotherapy drug, in the lymphodepletion regimen as a potential cause of the cardiac arrest. The argument is based on a 2017 paper that describes the case of a patient who died of acute heart failure after receiving a high dose of cyclophosphamide as part of an autologous stem cell transplantation treatment.

Many patients receive cyclophosphamide without suffering cardiac complications, but the analysts see reasons to think the subject enrolled in the Cellectis trial may have been at higher risk. Notably, prior exposure may increase risk, according to the analysts, suggesting the patients previous round of lymphodepletion may have been a factor.

Even if cyclophosphamide is at the heart of the problem, the analysts still think the UCARTCS1A dose is a contributing factor. With patients in the low-dose cohort also experiencing adverse events, the analysts see dosing at below 1 million cells per kilogram as one possible outcome of the situation.

Shares in Cellectis fell 13% in after-hours trading following news of the clinical hold. The value of Allogene Therapeutics, which licensed CAR-T assets that originated at Cellectis, held steady, likely reflecting a belief that the safety issue is limited to UCARTCS1A.

The Jefferies analysts see little or no read-through to other allogeneic programs, noting that the UCARTCS1A trial started at a higher dose than Cellectis two other clinical programs and that Allogene is testing several lymphodepletion regimens. The FDA placed a clinical trial of another Cellectis CAR-T, UCART123, on hold in 2017 after a patient died, but cleared it to resume months later.

Originally posted here:
Death in Cellectis off-the-shelf CAR-T trial triggers FDA hold - FierceBiotech

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