FDA Lifts Holds on "Off-the-Shelf" CAR-T Trials

The FDA today lifted clinical holds placed on 2 phase I trials investigating a gene-edited allogeneic CAR T-cell (UCART) therapy known as UCART123.

The agency halted UCART trials in September following the death of a 78-year-old man being treated for blastic plasmacytoid dendritic cell neoplasm (BPDCN). The FDA also cited the case of a 58-year-old woman who developed grade 3 cytokine release syndrome (CRS) and grade 4 capillary leak syndrome (CLS) while undergoing treatment for acute myeloid leukemia (AML). Both conditions eventually resolved after she was treated in an intensive care unit.

Paris-based biopharmaceutical company Cellectis is developing UCART123, a gene edited T-cell investigational drug targeting CD123, as a treatment for BPDCN and AML. It was designated an Investigational New Drug (IND) in February 2017, making it the first allogenic gene-edited CAR T-cell agent approved for clinical trial.

Unlike Novartis’s autologous CAR-T therapy tisagenlecleucel (Kymriah), UCART’s process is allogeneic and, in theory, could treat any patient using T cells harvested from any donor.

Cellectis says its “off-the-shelf” allogenic process is faster, easier to develop, and significantly less expensive than autologous CAR T-cell therapy—Novartis has set the price for a one-time treatment with its CAR-T cell therapy, tisagenlecleucel (Kymriah), at $475,000. The FDA approved tisagenlecleucel relapse in August for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

The company agreed to implement several provisions in the phase I UCART123 trials to lift the hold:

• Decrease the cohort dose level to 6.25 x 10⁴ UCART123 cells/kg
• Decrease the lymphodepleting regimen of cyclophosphamide to 750 mg/m² over 3 days, with a maximum daily dose of 1.33 grams of cyclophosphamide

• Include specific patient criteria at UCART123 infusion, such as no new uncontrolled infection after receipt of lymphodepletion, afebrile, only receiving a replacement dose of corticosteroids, and no organ dysfunction since eligibility screening
• Ensure the next 3 patients to be treated in each protocol will be under the age of 65
• Stagger enrollment across the UCART123 protocols AML123 and ABC123: at least 28 days should elapse between the enrollments of 2 patients across the 2 studies

Cellectis is working with investigators and clinical sites to obtain approval from its institutional review board on the revised protocols and resume patient enrollment.

Both patients cited by the FDA received 30 mg/m2 daily of fludarabine for 4 days and 1 g/m² daily of cyclophosphamide for 3 days as a preconditioning regimen. They then received 6.25 x 10⁵ UCART123 cells per kg, the first dose level explored in the protocol.

At day 5, the male patient experienced grade 2 CRS and grade 3 lung infection, which resolved following a dose of tocilizumab (Actemra), and administration of broad spectrum antibiotics. However, he developed a grade 5 CRS along with a grade 4 capillary leak syndrome 3 days later. Physicians administered corticosteroids and tocilizumab, as well as intensive care unit support, but he died on day 9.

In the case of the female patient, she developed an initial grade 2 CRS at day 8. By day 9, her CRS had worsened to grade 3 and she experienced grade 4 CLS. Her CRS resolved by day 11 following treatment management in intensive care unit, and her CLS resolved at Day 12. Neither patient experienced GVHD.

Patients have had success with allogenic CAR-T cell therapy in previous small studies. In phase I results published in 2013, donor-derived CD19-28z-CAR-T cells were used to treat 4 patients with chronic lymphocytic leukemia (CLL) and 6 with lymphoma, including 2 with diffuse large B cell lymphoma (DLBCL) and 4 with mantle cell lymphoma (MCL). Researchers observed no GVHD, grade 1 acute GVHD, or mild global score chronic GVHD.

Within 1 month after CD19-CAR-T cell infusion, one CLL patient achieved complete remission (CR), 6 patients (1 with CLL, 2 with DLBCL, and 3 with MCL) had stable disease. One patient with MCL partial remission, and two patients with CLL showed disease progression.

In another study, 8 patients were treated with allogeneic CD19-28z-CAR-T cells for B cell malignancies, 4 with CLL and 4 with ALL. All had experienced disease relapse or were at high risk of disease relapse after allogeneic-hematopoietic stem cells transplantation.

Researchers observed antitumor activity in 2 of 6 of the relapsed patients during the period of CD19-CAR-T cell persistence, whereas 2 patients who received cells while in remission remained disease-free. Of these 2 patients, 1 remained in CR for more than 8 months and the other remained in CR for 8 weeks after CAR-T infusion.

Liu, Zhong JF, Zhang X, Zhang C. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies. J Hematol Oncol. 2017;10(1):35. doi: 10.1186/s13045-017-0405-3.