On June 1, 2018 Celgene Corporation (NASDAQ:CELG) and bluebird bio, Inc. (NASDAQ:BLUE) reported updated results from the ongoing CRB-401 phase I clinical study of bb2121, an investigational anti-B-cell maturation antigen (BCMA) CAR T cell therapy, in 43 patients with late-stage relapsed/refractory multiple myeloma (Press release, bluebird bio, JUN 1, 2018, View Source [SID1234527043]). These data were the subject of an oral presentation by Noopur Raje, M.D. at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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"We are encouraged by the continuing deep and durable responses seen in this study and look forward to the results of our pivotal study, KarMMa, which is currently enrolling," said Jay Backstrom, Chief Medical Officer for Celgene. "We continue to see BCMA as an excellent target in multiple myeloma and we believe bb2121 has the potential to have a significant impact on the treatment approach and outcomes for these patients. We and our partners at bluebird bio are fully committed to the continued rapid clinical development of bb2121 and the evaluation of its potential in the treatment of patients with relapsed and refractory multiple myeloma."

"To see a median PFS of 11.8 months in this heavily pretreated patient population is very encouraging," said David Davidson, M.D., Chief Medical Officer, bluebird bio. "As the data from this program continue to mature, bb2121 has set a high bar as the leading investigational anti-BCMA CAR T cell candidate for relapsed and refractory multiple myeloma. In addition, the deep MRD-negative responses, the activity seen across myeloma with high and low levels of BCMA expression, as well as adverse events observed support the evaluation of bb2121 in earlier lines of multiple myeloma, where patients may experience more durable outcomes."

The open-label phase I CRB-401 study (NCT02658929) is evaluating the preliminary safety and efficacy of bb2121 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 bb2121 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 (≥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 (≥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 ≥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.

"The continuing high, durable response rates and MRD-negative results in this heavily pre-treated population of multiple myeloma patients further illustrates BCMA as a promising target in this incurable disease and bb2121 as an investigational therapy of great potential in patients with relapsed and refractory multiple myeloma with both high and low BCMA expression," said Dr. Raje., Professor of Medicine at Harvard Medical School and Director of the Multiple Myeloma Center at Massachusetts General Hospital. "We will continue to evaluate the long-term effect of bb2121 as we learn more about the potential for this investigational therapy."

bb2121 is an investigational compound that is not approved for any use in any country. bb2121 received Breakthrough Therapy Designation from the U.S. FDA and PRIME eligibility from the EMA. Celgene has also sponsored an open-label, single-arm, pivotal, phase 2 study (KarMMa), which is recruiting in North America and Europe, to evaluate bb2121 further in patients with relapsed and refractory multiple myeloma (NCT03361748).