Phase 1 of the study is comprised of an open-label, single ascending dose (SAD), multiple cohort study; a multiple dose cycle administration cohort study; and a combination administration study of P-BCMA-101 autologous T stem cell memory (Tscm) CAR-T cells in patients with relapsed / refractory MM. Followed by a Phase 2, open-label, efficacy and safety study. Rimiducid may be administered as indicated.
Phase 1 follows a 3 + 3 design of dose-escalating cohorts. Phase 2 of the study is an open-label multi-center efficacy and safety study. After a patient enrolls, leukapheresis will be performed to obtain peripheral blood mononuclear cells which will be sent to a manufacturing site to produce P-BCMA-101 CAR-T cells. The cells will then be returned to the investigational site and, after a standard chemotherapy based conditioning regimen, will be administered to the patient across 1-3 infusions, with or without combination therapy. Treated patients will undergo serial measurements of safety, tolerability and response. Rimiducid may be administered as indicated.
The following criteria is a partial list of reasons why patients may or may not be eligible to participate in this clinical trial. Further evaluation with a medical professional will be required to determine full eligibility.
The following criteria is provided for health care professionals.
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December 05, 2020
As of 30 Jun20, 43 patients had been treated with P-BCMA-101 (M/F 67%/33%, median age 60 years). Patients were heavily pre-treated (median of 7 prior regimens; range 3-18), with 100% having received proteasome inhibitors and IMiD, 93% daratumumab and 58% ASCT. This study was initially conducted as a dose escalation trial of single infusions of P-BCMA-101 from 0.75-15 x 106 cells/kg, preceded by standard lymphodepletion. Subsequently, exploratory cohorts with novel therapeutic strategies were evaluated. Using a modified manufacturing process, a median dose of 0.75 x 106 cells/kg were administered in cohorts including: P-BCMA-101 infusions in biweekly cycles; the addition of rituximab or lenalidomide pre- and post- lymphodepletion to prevent anti-CAR antibody development and increase T cell robustness, respectively; and single administration. The safety profile across the entire group was excellent for a CAR-T cell product which was attributed the gradual expansion of the Tscm cells (2-3 weeks to peak versus 3-7 days for most CAR-T cells). Cytokine release syndrome (CRS) was only seen in 17% of patients, with only one being grade 3 and one case of possible neurotoxicity reported (transient increase in confusion). Likewise, peak elevations of CRS markers were modest (maximum IL-6 level reported in any patient was 1631 pg/mL, orders of magnitude lower than levels frequently associated with severe CRS with CAR-T products). Only 3 patients required tocilizumab and no patients required ICU admission, safety switch activation or other aggressive measures. Based on the safety results the protocol was amended to allow fully outpatient CAR-T cell administration. There have been no patient deaths, DLTs or unexpected/off-target toxicities related to P-BCMA-101. The most common adverse events otherwise were cytopenias/infections and constitutional symptoms (≥ grade 3 neutropenia 79%, thrombocytopenia 30%, anemia 30%), as expected in CAR-T cell studies with lymphodepleting chemotherapy. Consistent with the high percentage of Tscm, circulating P-BCMA-101 cells were detected in blood by PCR, peaking at 2-3 weeks after infusion, and remaining detectable up to 1.5 years (ongoing at last follow-up). Response was seen to correlate with the Cmax and AUC of cell expansion, none of which correlated with dose administered.
The overall response rate (ORR) for evaluable subjects (n=34) treated with single administration during the initial dose escalation was 57%. As there was not a definite dose response curve, but indications of better response at lower doses, additional cohorts were implemented focusing on the lower end of the dose range using product from the modified manufacturing process. Four patients were subsequently treated with cyclic administration, rituximab, lenalidomide or single administration at the lowest dose level with this manufacturing process (all treated with P-BCMA-101 within ~2 months prior to the data cut-off date), and thus far all have rapidly responded (100% ORR) and all responses are ongoing. The safety profile in these patients (including multiply infused patients) was no different than the overall population, with minimal CRS reported.
May 13, 2019
According to results presented at the 2018 ASH Annual Meeting, 23 patients received treatment with P-BCMA-101 in 1 of 5 dose cohorts and no dose-limiting toxicities were observed at any dose.
All 3 patients who received P-BCMA at a mean dose of 857 x 106 achieved a response, with 2 achieving a very good partial response. The third patient achieved a partial response and minimal residual disease negativity. Seven patients received a mean dose of 456 x 106 and the objective response rate was 43% in these patients. In the 7 patients who received a mean dose of 152 x 106, the objective response rate was 71%. A minor response or better was seen in 13 of 19 evaluable patients by IMWG criteria.
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