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3389 Sequential T-Cell Engagement for Myeloma (“STEM”) Trial: A Phase 2 Study of Cevostamab Consolidation Following BCMA CAR T Cell Therapy

Program: Oral and Poster Abstracts
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
clinical trials, Biological therapies, Research, Bispecific Antibody Therapy, Plasma Cell Disorders, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, therapy sequence, Immunotherapy, Lymphoid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Adam D. Cohen, MD1, Wei-Ting Hwang, PhD2*, Sandra Susanibar-Adaniya, MD1, Dan T. Vogl, MD, MSCE1, Alfred L. Garfall, MD, MTR1, Adam Waxman, MD1*, Danielle Zubka, RN1*, Chau Nguyen, RN1*, Cynthia Diaczynsky1*, Marco Ruella, MD3, Michael C. Milone, MD, PhD4* and Edward A. Stadtmauer, MD1

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
2Department of Biostatistics, Epidemiology, and Informatics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
3Lymphoma Program, University of Pennsylvania, Philadelphia, PA
4Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA

Background and significance: The BCMA-targeted CAR T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are currently approved for relapsed/refractory multiple myeloma (RRMM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. However, despite unprecedented response rates, CAR T cells are not curative in these late-line patients, even for those in complete remission. Mechanisms of resistance may include lack of persistence or poor function of persisting CAR T cells, as well as BCMA-low or -negative residual tumor cells that serve as a reservoir for relapse. FcRH5 is another MM cell surface antigen, with expression independent of BCMA. Cevostamab is an FcRH5-targeted, T cell-engaging bispecific antibody (bsAb) with demonstrated activity in RRMM, including in patients with prior BCMA-directed therapies (Trudel et al, ASH 2021, #157). We hypothesize that consolidating BCMA CAR T cell therapy with a bsAb targeting a different antigen may re-invigorate persisting CAR+ T cells against residual BCMA+ tumor cells, while also activating endogenous T cells against FcRH5+, BCMA-low/negative tumor cells, ultimately improving rates of sustained minimal residual disease (MRD)-negativity and durability of response. Study design and methods: This is a single-institution, investigator-initiated study (NCT05801939) sponsored by the University of Pennsylvania, with funding support from Genentech. Targeted population are patients with RRMM who have received a commercially available CAR T cell product (ide-cel or cilta-cel) according to the FDA label, within the past 8 weeks, with stable disease or better. Major inclusion criteria include absolute neutrophil count ≥ 1, hemoglobin ≥ 7, platelets ≥ 50, and creatinine clearance ≥ 30 ml/min. Major exclusion criteria include prior cytokine release syndrome or ICANS ≥ grade 3, or any grade hemophagocytic lymphohistiocytosis (HLH) or Parkinsonism, or any active infection. The study schema is shown in Figure 1. Cevostamab is initiated 8-10 weeks after CAR T cell infusion. This timepoint was chosen to allow recovery from acute CAR T cell-related toxicities, but while CAR T cells may still be detectable in circulation. Cevostamab is given at a step-up dose of 3.6mg intravenously (IV) on Cycle 1, Day 1 (C1D1), followed by full dose of 160mg IV on C1D8. Subjects are hospitalized for 48 hours after each C1 dose to monitor for CRS and ICANS. They then continue cevostamab every 3 weeks for total of 8 cycles. If they are in an MRD-negative complete response (CR) after 8 cycles (Adaptive Clonoseq assay, at 10e-5 sensitivity), they stop therapy and are observed. If not, or if bone marrow results are indeterminate, they get another 8 cycles of cevostamab, then stop and are observed. The primary endpoint is frequency of MRD-negative CR at 12 months post-CAR T cell therapy. Assuming a roughly equal proportion of patients enrolling after ide-cel and cilta-cel, the null hypothesis is that the true MRD-negative CR rate at 12 months is 35%. Twenty-six evaluable subjects will be accrued in a single-stage design. The null hypothesis will be rejected if 14 or more subjects meet the primary endpoint. This design yields a one-sided type I error rate of 0.05 and power of 0.84 for an exact test when the true 12-month MRD-negative CR rate is 60%. Secondary endpoints include feasibility, safety/tolerability, and other efficacy measures (overall and CR rates, PFS, OS). Exploratory endpoints include 1) impact of cevostamab on pre- and post-therapy frequency and phenotype of both CAR+ and CAR-negative T cells in blood and marrow, assessed by multiparameter flow cytometry; 2) pre- and post-therapy expression of BCMA and FcRH5 on myeloma cells (when available), serum concentrations of soluble BCMA and FcRH5, and relationship of these factors to clinical outcome measures, and 3) pre- and post-therapy genotypic and phenotypic make-up of bone marrow microenvironment, assessed by single cell RNA sequencing (scRNAseq) and multiparameter flow cytometry, and relationship of these factors to clinical outcome measures. Conclusions: This phase 2 study is exploring the efficacy, safety, and feasibility of cevostamab consolidation following BCMA-directed CAR T cell therapy for RRMM, with the goal of sequential T cell engagement against 2 different antigens to eliminate residual disease. Accrual started in July 2023.

Disclosures: Cohen: Ichnos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Abbvie: Consultancy; Arcellx: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Novartis: Patents & Royalties, Research Funding. Vogl: Genentech: Consultancy; Karyopharm: Consultancy; Active Biotech: Research Funding; Takeda: Consultancy, Research Funding; GSK: Consultancy; Sanofi: Consultancy. Garfall: BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety and Monitoring Board; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Legend: Consultancy, Honoraria. Ruella: viTToria biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Founder, Research Funding; Beckman Coulter: Research Funding; GlaxoSmithKline: Consultancy; NanoString: Consultancy, Research Funding; AbClon: Consultancy, Research Funding; Bayer: Consultancy; Bristol Myers Squibb: Consultancy. Stadtmauer: Amgen: Consultancy; Janssen: Consultancy; genmab: Consultancy; Abbvie: Consultancy, Research Funding; BMS: Consultancy.

*signifies non-member of ASH