David Davidson, MD
An investigational anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy demonstrated an objective response rate (ORR) of 78% in patients with relapsed/refractory multiple myeloma, according to interim findings of a phase I dose-escalation study (NCT02658929).
Results of the first-in-human, open-label, multicenter trial, which were presented during the 27th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium December 1 in Munich, Germany, showed early promise for the novel therapy bb2121, with reports of clinical remissions and limited toxicity.
The treatment consists of autologous T cells that are transduced with a lentiviral vector that encodes a novel CAR incorporating an anti-BCMA single-chain variable fragment, a 4-1BB costimulatory motif, and a CD3-zeta T-cell activation domain.
“We are pleased that these early data from our ongoing phase I study of bb2121 demonstrate objective antitumor responses in heavily pretreated patients with multiple myeloma, with all patients in the 15.0 x 107
and 45.0 x 107
CAR+ T cell dose cohorts achieving responses, including among them, patients with stringent complete responses and elimination of minimal residual disease,” David Davidson, MD, chief medical officer of Bluebird Bio, the company developing bb2121 in collaboration with Celgene, said in a statement.
The phase I CRB-401 study enrolled heavily pretreated patients with multiple myeloma who received a median of 6 prior therapies. All patients previously received treatment with autologous stem cell transplant, as well as prior exposure to a proteasome inhibitor and an immunomodulatory agent. Also, 67% of patients were treated with daratumumab (Darzalex), 89% with lenalidomide (Revlimid), 78% with pomalidomide (Pomalyst), 100% with bortezomib (Velcade), and 78% received carfilzomib (Kyprolis). The median age of patients was 58 years; 67% were male.
Eleven patients were enrolled on the study and dosed in 4 dose cohorts: 5.0 x 107
(cohort 1), 15.0 x 107
(cohort 2), 45.0 x 107 (cohort 3), and 80 x 107
CAR+ T cells (cohort 4). All patients were evaluable for safety.
The first 9 patients, in the 5.0 x 107
, 15.0 x 107
, and 45.0 x 107
dose cohorts, underwent their first multiple myeloma tumor restaging and were also evaluable for efficacy.
The primary endpoint of the trial is incidence of adverse events (AEs) and abnormal laboratory test results, which include dose-limiting toxicities. Secondary endpoints include complete response, very good partial response (VGPR), and partial response (PR). Researchers involved in the study are also seeking to determine the recommended dose for additional clinical trials.
In the trial, patients were initially treated with a conditioning regimen of cyclophosphamide and fludarabine followed by the infusion of bb2121 anti-BCMA CAR T cells.
As of the data cutoff date, November 18, 2016, the ORR was 33% in cohort 1, followed by a 100% ORR in cohorts 2 and 3. In cohort 1, 1 patient had progressive disease, 1 had stable disease, and 1 had a PR.
In cohort 2, 2 patients had stringent complete responses; time to response was 2 months in 1 patient and 4 months in the other. One patient also experienced a VGPR and 2 patients were reported to have minimal-residual disease negativity after 1 month. In cohort 3, there were 3 PRs observed.
After 2 weeks or beyond, all patients enrolled in cohorts 2 and 3 who had bone marrow involvement at baseline had no detectable multiple myeloma cells in their bone marrow.
Regarding safety, no dose-limiting toxicities were observed. Additionally, there were no grade 3 or higher reports of neurotoxicity or cytokine release syndrome (CRS), and no patients were given tocilizumab or steroids to manage AEs.
Grade 1/2 CRS were observed in 67% of patients; the most common treatment-emergent AEs were neutropenia (89%), leukopenia (67%), and anemia (44%).
“We are also encouraged by the safety profile to date, particularly the lack of severe cytokine release syndrome or neurotoxicity,” said Davidson. “In light of these positive data, and thanks to the multiple participating clinical sites and centralized manufacturing infrastructure, we and our partner Celgene have built for this program, we anticipate efficiently completing the dose-escalation stage of the trial and initiating the expansion cohort.”
The CRB-401 trial is currently enrolling patients at 7 sites within the United States with an anticipated total enrollment of 50 patients.