Cellectis said the FDA has lifted the clinical hold placed in September on the company’s two Phase I studies of its universal gene-edited allogeneic chimeric antigen receptor T-cell (CAR-T) immunotherapy candidate UCART123 following the death of a patient in one of the trials.

The FDA clinical hold, announced September 4, applied to a trial (NCT03190278) assessing UCART123 in acute myeloid leukemia (AML)—as well as a trial assessing UCART123 in blastic plasmacytoid dendritic cell neoplasm (BPDCN).

In the BPDCN trial (NCT03203369), Cellectis acknowledged the death of a 78-year-old man treated with one prior therapy who showed relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) before undergoing treatment.

In return for the lifting of the clinical hold, Cellectis said, it agreed with the FDA to change its Phase I protocols. One change will reduce the cohort dose level to 6.25 x 104 UCART123 cells/kg—as recommended August 28 by the trials’ Data Safety Monitoring Board.

Other changes to the Phase I protocols:

  • Reducing the cyclophosphamide dose of the lympho-depleting regimen to 750 mg/m² per day over three days with a maximum daily dose of 1.33 grams of cyclophosphamide;
  • Implementing specific criteria for patients on the day of UCART123 infusion—namely no new uncontrolled infection after receipt of lymphodepletion, afebrile, off all but replacement dose of corticosteroids, and no organ dysfunction since eligibility screening;
  • Ensuring that enrollment will be staggered across the UCART123 protocols for the AML trial (AML123) and the BPCDN trial (ABC123)—and that at least 28 days should elapse between enrollments of two patients across both studies;
  • Ensuring that the next three patients to be treated in each protocol will be under the age of 65.

AML123 had been seeking adults ages 18 to 75, while adults ages 18 to 80 were eligible for ABC123.

In announcing the lifting of the clinical hold last night, Cellectis said it is working with investigators and clinical sites to obtain approval from the study’s independent review board on the revised protocols and resume patient enrollment—which has been listed for both trials as being suspended.

Primary Outcome Measures

The BPDCN trial’s primary outcome measures are the incidence, nature, and severity of adverse events and serious adverse events through day 84. Adverse events will be assessed according to common terminology criteria for adverse events and include cytokine release syndrome (CRS), tumor lysis syndrome (TLS), and graft-versus-host disease (GvHD), Cellectis stated on the trial’s page on ClinicalTrials.gov.

AML123 lists the same primary outcome, but adds that dose-limiting toxicities are assessed up to 42 days after UCART123 infusion. In announcing the clinical hold, Cellectis also disclosed an adverse event related to the first patient treated in the AML study—a 58-year-old woman, with 84% blasts in her bone marrow before initiating the conditioning regimen in advance of treatment.

On June 27, the company said, the patient received the same preconditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication. She experienced an initial grade 2 CRS eight days following treatment. The CRS worsened to grade 3 the following day, but was resolved on day 11 with treatment management in intensive care unit.

The female AML patient also experienced a grade 4 capillary leak syndrome nine days after treatment, a condition that was resolved on day 12, Cellectis added.

Cellectis launched the trials earlier this year after winning Investigational New Drug (IND) approval in February from the FDA to begin clinical testing. UCART123 is designed to target CD123, an antigen expressed at the surface of leukemic cells in AML, as well as on leukemic and other tumoral cells in BPDCN. According to Cellectis, UCART123 is the first allogeneic, “off-the-shelf,” gene-edited CAR T-cell product candidate approved by the FDA clinical trials.

Cellectis is not alone in reporting deaths tied to CAR-T therapies.

In March, Juno Therapeutics halted development of JCAR015, its lead CAR-T candidate indicated for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), four months after a second clinical hold was placed on a Phase II trial in which five patients died from cerebral edema.

And in May, months before its $11.9 billion acquisition by Gilead Sciences, Kite acknowledged the death of a patient in a trial of its CAR-T treatment Yescarta (axicabtagene ciloleucel; formerly KTE-C19) for relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) in patients who are ineligible for autologous stem cell transplant. The patient died due to cerebral edema following multiple organ failure—though Kite added that it was the only such case in 300-plus patients treated with the therapy, and that the patient showed rapidly progressing refractory NHL before being dosed.

The patient death did not stop Kite from winning FDA approval for Yescarta on October 18.

 

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