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1997 A Phase 1 Study of Two Investigational Agents, ACTR087, an Autologous T Cell Product Expressing an Antibody-Coupled T Cell Receptor, in Combination with SEA-BCMA, a Novel Non-Fucosylated Monoclonal Antibody, in Subjects with Relapsed or Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Biological, multiple myeloma, Diseases, Adult, Therapies, bioengineering, CAR-Ts, Technology and Procedures, Study Population, Plasma Cell Disorders, Lymphoid Malignancies
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Don M. Benson Jr., MD, PhD1, Houston Holmes, MD2*, Parameswaran Hari, MBBS, MD3, Jessica Sachs, MD4*, Ben Exter4*, Ann Ranger, PhD4*, Tooba Cheema, PhD4*, Iga Sienczylo, BS4*, Megan M. O'Meara, MD5, Django Sussman, PhD5* and Luke P. Akard, MD6

1Division of Hematology, The Ohio State University, Columbus, OH
2Texas Oncology/Baylor-Sammons Cancer Center, Dallas, TX
3Division of Hematology & Oncology, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI
4Unum Therapeutics Inc., Cambridge, MA
5Seattle Genetics, Bothell, WA
6Indiana Bone and Marrow Transplantation, Franciscan Health, Indianapolis, IN

Background: B cell maturation antigen (BCMA) has recently emerged as a promising candidate antigen for therapeutic targeting in multiple myeloma (MM), with several targeted agents in clinical studies including antibody-drug conjugates and bispecific T cell engagers as well as CAR T cells. The Antibody-Coupled T cell Receptor (ACTR) platform is a universal, engineered autologous T cell therapy developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct is composed of the ectodomain of CD16 fused to intracellular co-stimulatory and CD3ΞΆ signaling domains (Kudo et al., Cancer Res. 2014), which allow ACTR T cells to exert antibody-dependent cell-mediated cytotoxicity, a function otherwise physiologically limited to CD16-expressing natural killer cells and macrophages.

ACTR087 expresses a 4-1BB-containing receptor and has been evaluated in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ B cell lymphoma as previously reported (Akard et al., Blood 2017). SEA-BCMA is a novel, humanized non-fucosylated anti-BCMA IgG1 antibody that has been demonstrated pre-clinically to bind to ACTR087 T cells to mediate ACTR T cell activation, cytotoxicity, cytokine release, and proliferation in the presence of BCMA-expressing MM cell lines. These functional activities were demonstrated to be BCMA-specific and SEA-BCMA dose-dependent (Cheema et al., AACR 2017). Here we present preliminary findings from the first 2 single-subject cohorts of the ATTCK-17-01 study (NCT03266692), an ongoing Phase 1 study of ACTR087 in combination with the first-in-human administration of SEA-BCMA.

Methods: ATTCK-17-01 is a multicenter, Phase 1, dose-escalation study of ACTR087 in combination with SEA-BCMA. The primary objectives are to characterize the safety and to determine the recommended Phase 2 dose of ACTR087 in combination with SEA-BCMA in subjects with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, ACTR T cell persistence, cytokines, and SEA-BCMA pharmacokinetics (PK); exploratory objectives include the anti-myeloma activity of SEA-BCMA alone. Subjects must have measurable disease and must have received at least 3 prior lines of therapy including treatment with a proteasome inhibitor and an immunomodulatory agent, and hematopoietic stem cell transplant (HSCT) for HSCT-eligible subjects. BCMA expression on MM cells was not a condition of eligibility. Dose escalation of the 2 investigational agents, ACTR087 and SEA-BCMA, is determined according to adaptive design principles.

After study enrollment and leukapheresis, subjects receive SEA-BCMA by IV infusion once every 3 weeks until disease progression or treatment discontinuation. After the third dose of SEA-BCMA and lymphodepleting chemotherapy (cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2, each daily for 3 days), subjects receive a single dose of ACTR087.

Results: Two subjects enrolled and received ACTR087 at the first dose level in combination with the first 2 dose levels of SEA-BCMA. First-in-human dosing of SEA-BCMA was well tolerated, with no reported SEA-BCMA-related adverse events (AEs) or dose-limiting toxicities (DLTs).

Following ACTR087 infusion, ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. No DLTs were observed with the combination of ACTR087 and SEA-BCMA in the first 2 cohorts. Grade 3 or higher treatment-emergent AEs experienced by at least 1 subject, regardless of causality assessment, include cytopenias, increased ALT, and bone pain.

Conclusions: ACTR087 in combination with SEA-BCMA was well tolerated in the first 2 subjects treated, with no DLTs or AEs leading to treatment discontinuation. These results support the continued dose escalation of ACTR087 in combination with SEA-BCMA. Enrollment in Cohort 3 is ongoing. Updated data, including SEA-BCMA PK, biomarkers, and preliminary Cohort 3 data, will be presented.

Disclosures: Holmes: Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Hari: Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding. Sachs: Unum Therapeutics Inc.: Employment. Exter: Unum Therapeutics Inc.: Employment. Ranger: Unum Therapeutics Inc.: Employment. Cheema: Unum Therapeutics Inc.: Employment. Sienczylo: Unum Therapeutics Inc.: Employment. O'Meara: Seattle Genetics: Employment, Equity Ownership. Sussman: Seattle Genetics: Employment. Akard: Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

*signifies non-member of ASH