S263: PHASE I OPEN-LABEL SINGLE ARM STUDY OF GPRC5D CAR-T CELLS (ORICAR-017) IN PATIENTS WITH RELAPTSED/REFRACTORY MULTIPLE MYELOMA (POLARIS)

Abstract

Background: G-protein–coupled receptor class 5-member D (GPRC5D), a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cell phenotype, including most malignant plasma cells from pts with multiple myeloma (MM). The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the standard second generation CAR-T cell with improvement in expansion and durability of CAR-T cells post-transfusion. Here we report initial results from the phase I open-label single arm study of GPRC5D CAR-T Cells (OriCAR-017) in pts with Relapsed/Refractory (R/R) MM (NCT05016778). Aims: The primary objective in the dose escalation phase was to evaluate safety and tolerability of OriCAR-017. Secondary endpoints included efficacy and pharmacokinetics (expansion and persistence of OriCAR-017. Methods: Key enrolment criteria included adults with measurable MM, R/R or intolerant to established MM therapies, prior BCMA-targeted therapy allowed. Patient received lymphodepleting chemotherapy with Fludarabine 30mg/m2 daily and cyclophosphamide 300mg/m2 daily for 3 days followed by a single infusion of OriCAR-017. The trial followed a standard 3 + 3 design with the following dose cohorts: 1×106/kg, 3×106/kg and 6×106/kg CAR+ T cells. Results: Eleven pts with R/R MM were enrolled and underwent apheresis during June 9, 2021 and February 25, 2022. Nine of them have completed OriCAR-017 infusion to date. 2 pts were suspended infusion due to rapid disease progression. Of the 9 pts infused, median age of 65 years (range: 41-71) and a median of 6 (range 3-17) prior lines of therapy; 4 (44.4%) prior BCMA CART therapy. 3 (33.3%) pts with extramedullary plasmacytoma ≥ 1 and 7 (77.8%) pts with bone marrow plasma cells ≥60% at baseline. Five out of 6 pts had high-risk cytogenetic profiles, including 2 pts with del(17p). No dose-limiting toxicities occurred. The most common treatment-related AEs were hematological toxicities. All pts experienced Cytokine Release Syndrome (CRS, with 8(88.9%) pts in G1, 1 (11.1%) patient in G2), no G3/4 CRS was observed. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. No neurologic toxicities were reported to date. All 9pts median follow up time was 118 days (range33—220). A 100.0% ORR were observed with 3 (33.3%) pts achieved CR/sCR, 3 pts (33.3%) were VGPR, 3 pts were PR (33.3%). 4 pts relapsed from BCMA CAR-T therapy had responses with 1 sCR, 2 VGPR, 1 PR. All 9 pts were Minimal Residual Disease (MRD) negative in the bone marrow by flow cytometry (sensitivity: 10-5) at day 28 after infusion, and 6pts continued MRD negative at month 3 and 2 pts at month 6 after infusion. Robust OriCAR-017 expansion in peripheral blood by using qPCR in 3 dose cohorts, median peak was 349866.1copies/ml (range 60837.5 – 2240358.5), median time to peak expansion was 10 days (range 7-14). 8 out of 9 patients detected CAR + cell in bone marrow at D28 after infusion with median 498048.3copies/ml (range 495.4- 2358538.6). Image:Summary/Conclusion: In this phase I study, OriCAR-017 was safe and showed impressive efficacy among previously heavily treated R/RMM pts. Majority of AEs were transient, manageable, and reversible. 100% ORR and 100% MRD negative rate, along with favorable safety evidenced support OriCAR-017 could be a competitive therapy for pts with R/RMM. Furthermore, pts who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017 treatment.