Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME)

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (T_SCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 10⁶ P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 10⁶ cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study.

A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be >=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 10⁶ P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m²/day) / fludarabine (30 mg/m²/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials.

Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM).