Phase 1/2 Study of the Safety and Response of P-BCMA-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME) with Novel Therapeutic Strategies
Authors: Costello Caitlin L. , Cohen Adam D. , Patel Krina K. , Ali Syed S , Berdeja Jesus G. , Shah Nina , Ganguly Siddhartha , Kocoglu Mehmet Hakan , Abedi Mehrdad , Ostertag Eric M. , Martin Chris E , Ghoddussi Majid , Shedlock Devon J , McCaigue Joanne , Namini Hamid , Yalamanchili Sreeni , Spear Matthew A. , Gregory Tara K. 
Published: November 2020

P-BCMA-101 is an autologous chimeric antigen receptor-T cell (CAR-T) therapeutic targeting BCMA and comprised of a high percentage of desirable stem cell memory T cells. P-BCMA-101 is manufactured using a novel transposon-based system called piggyBac and is designed to increase efficacy while minimizing toxicity.
A phase 1/2, clinical trial is being conducted in patients with r/r MM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory) to assess the safety and efficacy of P-BCMA-101 (NCT03288493). No pre-specified level of BCMA expression was required. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients intravenously (IV) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) lymphodepletion regimen.
As of 30Jun20, 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.
In conclusion, current clinical data are consistent with preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, with remarkably low toxicity allowing for outpatient administration. Low doses appear highly efficacious and the modifications to manufacturing appear to have notably improved efficacy.

Disclosures
Costello: Poseida Therapeutics: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Patel:Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectis: Research Funding. Berdeja:Lilly: Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bioclinica: Consultancy; Glenmark: Research Funding; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird: Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Teva: Research Funding; Servier: Consultancy; Amgen: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Constellation: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Ganguly:Kadmon: Other: Ad Board; KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Yalamanchili:Poseida Therapeutics: Current Employment, Current equity holder in private company. Gregory:Kesios: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Celularity: Research Funding; Teva: Research Funding; Vivolux: Research Funding; Lilly: Research Funding; Constellation: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CRISP Therapeutics: Research Funding; CURIS: Research Funding; Acetylon: Research Funding; Incyte Corporation: Consultancy; Bluebird: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding.