CRB-401 phase I clinical study of bb 2121 for multiple myeloma led to a median PFS of 11.8 months among those patients who received an active dose of the cell therapy.-- Celegene + bluebird bio.

Celgene Corporation and bluebird bio, Inc. announced updated results from the ongoing CRB-401 phase I clinical study of bb 2121, an investigational anti-B-cell maturation antigen (BCMA) CAR T cell therapy, in 43 patients with late-stage relapsed/refractory multiple myeloma. These data were the subject of an oral presentation by Noopur Raje, M.D. at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.

The open-label phase I CRB-401 study (NCT02658929) is evaluating the preliminary safety and efficacy of bb 2121 anti-BCMA CAR T cell therapy in patients with relapsed/refractory multiple myeloma. Patients in the study were heavily pre-treated, with a median of seven prior myeloma treatment regimens (min, max: 3,14) in the dose escalation cohort (n=21) and eight prior regimens (min, max: 3, 23) in the dose expansion cohort (n=22). More than 90% of patients had received prior treatment with two IMiD therapies, two proteasome inhibitors, daratumumab and an autologous stem cell transplant.

As of the March 29, 2018 data cut-off, 43 patients had been enrolled and dosed in either the dose-escalation cohort of the study, at four dose levels (50 x 106, 150 x 106, 450 x 106 and 800 x 106 CAR+ T cells), or in the dose expansion cohort in a dose range between 150-450 x 106 CAR+ T cells. Patients received a lymphodepleting conditioning regimen of fludarabine and cyclophosphamide, followed by an infusion of bb 2121 anti-BCMA CAR T cells. The CAR T cells were produced from each patient's own blood cells, which were modified using a proprietary lentiviral vector encoding the anti-BCMA CAR. Responses were dose-related and observed for both low and high BCMA expression levels.

In patients treated with 450 x 106 CAR+ T cells whose myeloma cells expressed low levels of BCMA (0 to 50% of cells BCMA positive), 8 of 8 had a response. In those expressing high BCMA ( greater than 50% BCMA positive), 10 of 11 had a response. The median progression-free survival (PFS) estimate for patients in the dose-escalation phase treated at active doses ( greater than 150 x 106 CAR+ T cells) was 11.8 months (95% CI 8.8, NE), while patients receiving 50 x 106 CAR+ T cells had a median PFS of 2.7 months (95% CI 1.0, 2.9). In the dose-escalation and expansion phase of the study, all patients who responded and were evaluable for minimal residual disease (MRD as measured by adaptive next-generation sequencing assay) (n=16) were MRD negative at one or more time points. Additionally, two patients who did not have a response and were evaluated for MRD were MRD positive at month one. The median PFS estimate in MRD negative responders was 17.7 months (95% CI: 5.8, NE).

Among all infused patients (n=43), 63% had cytokine release syndrome (CRS), mostly Grade 1 & 2, with 2 patients experiencing Grade 3 CRS (5%). Nine patients (21%) received tocilizumab, including 4 patients (9%) who also received steroids and the median duration of CRS was 6 days (1,32). For patients receiving 150 x 106 CAR+ T cells (n=18), the rate of CRS was 39% with no grade 3 cases. For patients receiving greater than 150 x 106 CAR+ T cells (n=22), the rate of CRS was 82% with 9.1% of patients experiencing grade 3 events. Also among all infused patients, there were 14 patients (33%) who experienced neurotoxicity, with one patient experiencing a grade 3 or higher event. Other frequent Grade 3/4 AEs included cytopenias commonly associated with lymphodepleting chemotherapy such as neutropenia (79%), thrombocytopenia (51%) and anemia (44%), as well as infection (any grade) with a frequency of 61% overall and 23% in the first month. Grade 3 or higher infection occurred with a frequency of 21% overall and 5% in the first month.

Comment: The issue is how CAR-T therapy's efficacy holds up over time. For that matter bb 2121's progression-free survival mark of 11.8 months comes in roughly at analyst expectations, albeit toward the lower end.