Date: 2018-06-01
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Bluebird bio (USA - MA) Celgene (USA - NJ)
Product: bb2121 anti-BCMA CAR T cells
Action
mechanism:
Disease: multiple myeloma
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details:
Latest
news: 50 x 106 (n=3), median follow-up 84 days (59,94) 150 x 106 (n=14), median follow-up 87 days (36,638) >150 x 106 (n=22), median follow-up 194 days (46, 556) Overall response (ORR) Complete response (CR) Very good partial response (VGPR) Median duration of response mDOR *Patients with ?2 months of response data or PD/death within <2 months Number of
Patients
Evaluable for
Efficacy SD (1 patient) PR (1 patient) CR (2 patients; 1
patient MRD
negative)
VGPR (1 patient
MRD negative)
PR (1 patient) CR (1 patient*)
VGPR (5
patients; 1 patient MRD
negative)
PR (2 patients;
1 patient MRD
negative) *Patient died of
unrelated cardio
pulmonary arrest PR (1 patient) CR (1 patient) All patients in cohorts 2, 3 and 4 with bone marrow
involvement at baseline had no detectable multiple
myeloma cells in their bone marrow on Day 14 or beyond.
Of four patients evaluable for MRD status, all four were found to be
MRD-negative. Median Prior
Lines of
Therapy 7 (range: 3-14); all patients had at least one prior autologous stem cell
transplant, as well as prior exposure to a proteasome inhibitor and an
immunomodulatory agent; 71% of patients had previously received
daratumumab or CD38 antibody. 15/21 (71%) of patients had CRS, mostly Grade 1 & 2; 2 patients with
Grade 3 CRS that resolved within 24 hours. 4 patients received
tocilizumab, 1 (Grade 2 CRS) received steroids. The most common
treatment-emergent Grade 3-4 AEs in 21 infused patients include
cytopenias commonly associated with cy/flu lymphodepletion, as well
as Grade 3 events of hyponatraemia (n=4), cytokine release syndrome
(n=2), upper respiratory infection (n=2), and syncope (n=2).
• On June 1, 2018, Celgene and bluebird bio announced 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. 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. 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 106CAR+ 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.
Response outcomes in efficacy evaluable patients* in the study were as follows:
Patients on study were heavily pre-treated, with a median of 7 prior therapies (range: 3 - 14):
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.
• On December 10, 2017, Celgene and bluebird bio announced that updated results from the ongoing CRB-401 Phase 1 clinical study of bb2121 in 21 patients with late-stage relapsed/refractory multiple myeloma will be presented in an oral presentation at the American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: Updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy (Abstract #740). James Kochenderfer, M.D., the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland
Measure
33.3%
57.1%
95.5%
0%
42.9%
50%
0%
7.1%
36.4%
1.9 months
Not estimable
10.8 months
As of the October 2, 2017 data cut-off, 21 patients had been enrolled and dosed in the dose-escalation phase of the study, in four dose cohorts: 50 x 106, 150 x 106, 450 x 106 and 800 x 106 CAR+ T cells. This multi-center study has enrolled patients at nine sites in the U.S with central manufacturing performed at Celgene.
Patients received a conditioning regimen of cyclophosphamide and fludarabine, 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.
Results in the active dose cohorts (150 x 106, 450 x 106 and 800 x 106 CAR+ T cells; N=18) were:
In the dose-escalation phase, 15/21 (71%) of patients had cytokine release syndrome (CRS), mostly Grade 1 & 2, with 2 patients experiencing Grade 3 CRS (9%). Four patients received tocilizumab, 1 (Grade 2 CRS) received steroids and in each case the CRS resolved within 24 hours. The most common treatment-emergent Grade 3-4 AEs in 21 infused patients were cytopenias commonly associated with lymphodepleting chemotherapy including neutropenia (86%), anemia (57%) and thrombocytopenia (43%). There were two deaths in the active cohorts at 22 and 69 weeks following infusion, respectively. The first was due to cardiac arrest and the second was due to myelodysplastic syndrome; both subjects were in a myeloma CR at their last study assessment prior to death. Based on the findings during dose escalation, a dose expansion phase of 12 subjects has started testing doses between 150-450 x 106 CAR+ T cells. In the dose expansion phase, one patient treated at the 450 x 106 CAR+ T cells dose experienced Grade 4 neurotoxicity including focal cerebral edema and subarachnoid hemorrhage. This patient had a high tumor burden, and a history of subarachnoid hemorrhage. The event was successfully managed, and the patient remains in the response group. No other Grade 3/4 neurotoxicity was observed in the escalation or expansion cohort.
• On June 5, 2017, bluebird bio and Celgene announced that updated results from the ongoing CRB-401 Phase 1 clinical study of bb2121 in 18 patients with relapsed/refractory multiple myeloma will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. The objective of this Phase 1 dose-escalation study is to evaluate safety and efficacy of bb2121 and determine a recommended Phase 2 dose. Patients on study were heavily pre-treated, with a median of seven prior therapies (range: 3 - 14). As of the May 4, 2017 data cut-off, 21 patients had been enrolled and dosed in four dose cohorts: 50 x 106, 150 x 106, 450 x 106 and 800 x 106 CAR+ T cells. All 21 dosed patients were evaluable for safety, and 18 patients have undergone their first multiple myeloma tumor restaging and were evaluable for efficacy. This study has enrolled patients at seven sites in the U.S., with an anticipated total enrollment of up to 50 patients.
Patients received a conditioning regimen of cyclophosphamide and fludarabine, 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 lentiviral vector encoding the anti-BCMA CAR.
Results, as of May 4, 2017 Data Cut-off:
• On May 17, 2017, bluebird bio announced that updated interim data from its study of bb2121 will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. (First-in-Human Multicenter Study of bb2121 anti-BCMA CAR T Cell Therapy for Relapsed/Refractory Multiple Myeloma: Updated Results - Abstract #3010).
Cohort
1
2
3
4
CAR+ T Cell Dose
50 x 106
150 x 106
450 x 106
800 x 106
3
4
8
3
Overall Response Rate in Cohort
33%
100%
100%
100%
Best Response
PD (1 patient)
VGPR (1 patient)
Safety
