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      Phase 1 Study of CART-ddBCMA, a CAR-T therapy utilizing a novel synthetic binding domain, for the treatment of subjects with relapsed and refractory multiple myeloma.

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          Abstract

          8015

          Background: CART-ddBCMA is an autologous CAR-T cell therapy encoding a novel non-scFv synthetic binding domain targeting BCMA with a 4-1BB costimulatory motif and CD3-zeta T-cell activation domain. The novel binding domain is based on a computationally-derived triple-helix protein scaffold that is small (73 amino acids), stable, engineered to reduce immunogenicity, and can be modified to bind alternative targets. Methods: ARC-101 (NCT04155749), ARM 1 (CART-ddBCMA) is a Phase 1, multi-center, open-label, dose escalation trial enrolling subjects who have received ≥3 prior regimens, including proteasome inhibitor(s), immuno-modulatory agent(s), and anti-CD38 antibody, or are triple-refractory. Subjects undergo lymphodepletion with fludarabine and cyclophosphamide, then receive CART-ddBCMA as a single infusion. Planned dose levels are 100, 300, and up to 900 x 10 6 CAR+ T cells. The primary endpoint is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Secondary endpoints include clinical response per IMWG criteria, MRD, DOR, PFS, OS, and CAR-T cell kinetics. Results: As of 29 Jan 2021, 10 subjects received CART-ddBCMA, 9 subjects were evaluable, and 1 subject was pending assessment. Median age was 66 years [min:max 54 to 75]. 6 subjects received 100 x 10 6 CAR+ T cells, and 4 subjects received 300 x 10 6 CAR+ T cells. Median CAR+ expression was 74.5% (min:max 61-87%) of total T cells. Of the evaluable subjects, median follow-up after cell infusion was 208 days (min:max 45 to 355+ days), 9/9 subjects were penta-refractory, 1 subject was also refractory to BCMA-directed ADC. 8/9 had high-risk cytogenetics (1 subject’s sample not evaluable), and 6/9 subjects had extramedullary disease. No DLTs were reported. Per ASTCT Consensus Grading (Lee et al, 2019), 8 subjects developed G1/2 CRS, 1 subject in the higher dose cohort developed G3 CRS that rapidly resolved with tocilizumab. 1 subject developed G2 ICANS which rapidly resolved with intervention. 7 subjects received tocilizumab; 3 received dexamethasone. ORR was 100% (9/9) per IMWG criteria including 4 sCR, 1 VGPR, and 4 PR. 1 subject with PR relapsed and was retreated. All other subjects have ongoing responses; observations included sFLC normalization and elimination of detectable bone marrow disease by Month 1. Ongoing responses for subjects not yet achieving CR continue to deepen. 7 subjects were evaluable by MRD of which 5 are MRD-negative, and 2 are pending results. CAR-T cell expansion, as measured by vector transgene copies per microgram genomic DNA was observed in all patients. Conclusions: Early efficacy results are encouraging, with 9/9 (100%) ORR and manageable toxicities. 8/9 responses are ongoing and responses continue to deepen. These data are encouraging in high-risk subjects with penta-refractory myeloma. Subjects continue to be enrolled and treated. Clinical trial information: NCT04155749.

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          Author and article information

          Journal
          Journal of Clinical Oncology
          JCO
          American Society of Clinical Oncology (ASCO)
          0732-183X
          1527-7755
          May 20 2021
          May 20 2021
          : 39
          : 15_suppl
          : 8015
          Affiliations
          [1 ]Massachusetts General Hospital Cancer Center, Boston, MA;
          [2 ]Massachusetts General Hospital, Harvard Medical School, Boston, MA;
          [3 ]Massachusetts General Hospital, Charlestown, MA;
          [4 ]Beth Israel Deaconess Medical Center, Boston, MA;
          [5 ]University of Chicago, Chicago, IL;
          [6 ]The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL;
          [7 ]Dana-Farber Cancer Institute, Boston, MA;
          [8 ]Dana Farber Cancer Institute, Cell Manipulation Core Facility, Boston, MA;
          [9 ]CE3, Clinton, CT;
          [10 ]Arcellx, Gaithersburg, MD;
          [11 ]Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
          Article
          10.1200/JCO.2021.39.15_suppl.8015
          b08f4726-1ad7-47c2-a59a-4968871faeb3
          © 2021
          History

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