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3199 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

Program: Oral and Poster Abstracts
Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
Biological, Adult, bioengineering, Therapies, CAR-Ts, Elderly, gene therapy, Technology and Procedures, immunotherapy, gene editing, Study Population, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Matthew J Frigault, MD, MSc1, Michael R. Bishop, MD2, Elizabeth K. O'Donnell, MD3, Noopur S. Raje, MD4, Allegra Mondillo5*, Daniella Cook5*, Heather Daley6*, Carissa Mangus7*, David W LeFleur8*, Janine M Buonato8*, Justin P Edwards9*, Laura K Richman, DVM, PhD10*, Maria T Polianova, PhD10*, Maria Sabatino, MD10*, Scott Currence10*, Angela Shen, MD10*, Travis Quigley, MS9* and Marcela V. Maus, MD, PhD11

1Blood and Marrow Transplant Program, Massachusetts General Hospital / Harvard Medical School, Dorchester, MA
2Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
3Massachusetts General Hospital Cancer Center, Boston, MA
4Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, MA
5Cancer Center, Massachusetts General Hospital, Boston, MA
6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
7CE3, Inc.,, Clinton, CT
8Arcellx, Inc, Gaithersburg, MD
9Arcellx, Inc., Gaithersburg
10Arcellx, Inc., Gaithersburg, MD
11Massachusetts General Hospital, Harvard Medical School, Boston, MA

Introduction: Chimeric Antigen Receptor (CAR) T cell therapies directed against B-cell maturation antigen (BCMA) have demonstrated compelling clinical activity and manageable safety in subjects with relapsed and refractory Multiple Myeloma (RRMM). These CAR T cells encode humanized or murine scFvs, or camelid heavy chain antibody fragments with CD3-zeta in combination with 41BB or CD28 co-stimulatory domains. In contrast, CART-ddBCMA is an anti-BCMA investigational CAR T cell therapy encoding a non-scFv, synthetic binding domain targeting BCMA with a 4-1BB costimulatory motif and CD3-zeta T cell activation domain. The binding domain is a small stable protein comprising 73 amino acids engineered to reduce the risk of immunogenicity. CART-ddBCMA is being studied as part of a Master Phase 1 Cell Therapy protocol for RRMM and is a first-in-human clinical study to assess the safety, pharmacokinetics, immunogenicity, efficacy, and duration of effect.

Methods: ARC-101 (NCT04155749), ARM 1 (CART-ddBCMA) is a Phase 1, multi-center, open label, dose escalation trial enrolling approximately 12 subjects with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor, an immuno-modulatory agent, and a CD38 antibody or are triple-refractory. There is no prescreening or requirement for BCMA expression on tumor cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for selection, transduction, and expansion on the CliniMACS Prodigy® system. The drug product is cryopreserved and undergoes release testing prior to being returned to the site for infusion. Subjects undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive CART-ddBCMA as a single infusion. Planned dose levels are 100, 300, and 900 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ cells in blood.

Results: As of July 1, 2020, 4 subjects (median age 73.5 [min;max 73 to 75]) were enrolled and 4 received CART-ddBCMA. Median follow-up after CART-ddBCMA infusion was 100 days (min:max 9 to 142 days), 3 subjects were evaluable for initial safety and clinical response and 1 subject was pending assessment. All subjects received a dose of 100 x 106 CAR+ T cells±20%, median drug product CAR+ expression was 76% (min:max 72-78%) of total CD3+ T cells. Subjects had a median of 5 (min;max 5 to 7) prior lines of therapy and one had prior autologous stem cell transplant; one had high-risk cytogenetics. All 4 subjects had previously received Bort/Len/Car/Pom/Dara and 2 were penta-refractory. Three subjects had high tumor burden, with 95, 95, and 70% bone marrow plasma cells pre-infusion, respectively. Three subjects developed Grade 2 cytokine release syndrome (CRS) and 1 subject developed Grade 2 ICANS. These adverse effects resolved quickly after intervention; 3 subjects received tocilizumab and 2 received steroids (dexamethasone). All 3 evaluable subjects have demonstrated clinical response per IMWG criteria: currently 1 sCR (MRD-10-4), 1 sCR, 1 sCR (MRD-10-6). MRD negative results were obtained by next-generation sequencing (Adaptive clonoSEQ), 1 subject did not have baseline bone marrow involvement. Extramedullary disease resolved in three subjects. CAR+ T cell expansion during the first 30 days was observed in evaluable subjects by ddPCR. No post treatment ADA were detected in the first 3 subjects, through M1.

Conclusions: In the initial cohort receiving 100 x 106 CAR+ T cells of CART-ddBCMA, no subjects experienced severe CRS and/or ICANs. Early efficacy results are encouraging, with all 3 evaluable subjects demonstrating deep clinical responses of sCR, with 2 MRD negative bone marrow responses at 1 month. No evidence of ADA has been detected to date. These data are encouraging in a small group of elderly subjects who did not initially receive autologous transplant following induction therapy. Subjects continue to be enrolled and treated. Additional subjects, and longer follow-up will establish whether treatment with CART-ddBCMA results in durable CAR+ T responses.

Disclosures: Frigault: Celgene: Consultancy; Novartis: Consultancy, Research Funding; Arcellx: Consultancy; Gilead/Kite: Consultancy, Research Funding. Bishop: Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRSPPR Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Speakers Bureau. O'Donnell: Celgene: Consultancy. Raje: Celgene: Consultancy. LeFleur: Arcellx: Current Employment, Current equity holder in private company. Buonato: arcellx: Current Employment, Current equity holder in private company. Edwards: arcellx: Current Employment, Current equity holder in private company. Richman: arcellx: Current equity holder in private company. Polianova: arcellx: Current Employment, Current equity holder in private company. Sabatino: Arcellx: Current equity holder in private company. Currence: Arcellx: Current Employment, Current equity holder in private company. Shen: Arcellx: Current Employment, Current equity holder in private company. Quigley: Arcellx: Current Employment, Current equity holder in private company. Maus: Novartis: Consultancy, Research Funding; kite: Consultancy, Research Funding; arcellx: Consultancy, Research Funding; tcr2: Consultancy, Current equity holder in publicly-traded company; century therapeutics: Current equity holder in private company.

*signifies non-member of ASH