Novel Agent Shows Promising Response Rates in Multiple Myeloma

According to interim findings of a phase 1 dose escalation trial, an investigational anti—B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy demonstrated an objective response rate (ORR) of 78 percent in patients with relapsed/refractory multiple myeloma

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 Dec. 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 1 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, M.D., chief medical officer of Bluebird Bio, the company developing bb2121 in collaboration with Celgene, said in a statement.

The phase 1 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 percent of patients were treated with Darzalex (daratumumab), 89 percent with Revlimid (lenalidomide), 78 percent with Pomalyst (pomalidomide), 100 percent with Velcade (bortezomib) and 78 percent received Kyprolis (carfilzomib). The median age of patients was 58 years; 67 percent were male.

Eleven patients were enrolled on the study and dosed in four 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 nine 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, Nov. 18, 2016, the ORR was 33 percent in cohort 1, followed by a 100 percent ORR in cohorts 2 and 3. In cohort 1, one patient had progressive disease, one had stable disease and one had a PR.

In cohort 2, two patients had stringent complete responses; time to response was two months in one patient and four months in the other. One patient also experienced a VGPR and two patients were reported to have minimal-residual disease negativity after one month. In cohort 3, there were three PRs observed.

After two 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 percent of patients; the most common treatment-emergent AEs were neutropenia (89 percent), leukopenia (67 percent) and anemia (44 percent).

“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 seven sites within the United States with an anticipated total enrollment of 50 patients.