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3313 Phase 1 Study of CART-Ddbcma for the Treatment of Subjects with Relapsed and /or Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Biological therapies, clinical trials, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, Therapies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Matthew Frigault, MD, MS1, Jacalyn Rosenblatt, MD2, Binod Dhakal, MBBS3, Noopur Raje, MD4, Daniella Cook, BS5*, Mahmoud R. Gaballa, MD6, Estelle Emmanuel-Alejandro7*, Danielle Nissen8*, Christine Cornwell9*, Kamalika Banerjee9*, Anand Rotte, PhD9*, Christopher R. Heery, MD9, David Avigan, MD10, Andrzej Jakubowiak, MD, PhD11 and Michael R. Bishop, MD12

1Massachusetts General Hospital, Dorchester, MA
2Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
3Medical College of Wisconsin, Division of Hematology/Oncology, Department of Medicine, Milwaukee, WI
4Mass General Hospital Cancer Center, Boston, MA
5Cancer Center, Massachusetts General Hospital, Boston, MA
6Massachusetts General Hospital, Boston, MA
7Massachusetts General Hospital Cancer Center, Boston
8Medical College of Wisconsin, Milwaukee
9Arcellx, Inc., Gaithersburg, MD
10Beth Israel Deaconess Medical Center, Boston, MA
11Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
12The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL

Introduction: B-cell maturation antigen (BCMA) targeting chimeric Antigen Receptor (CAR) T cell therapies have shown compelling clinical activity and manageable safety in subjects with relapsed and/or refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy with a unique, synthetic binding domain targeting BCMA, instead of the typical scFv approach, a 4-1BB costimulatory motif, and CD3-zeta activation domain. The binding domain is a small stable protein, called a D-Domain, comprising 73 amino acids. CART-ddBCMA is being studied in a first-in-human clinical study.

Methods: This Phase 1, multi-center, open label, dose escalation trial enrolling subjects with RRMM who have received ≥3 prior regimens, including a proteasome inhibitor, an Immune-modulatory agent, and a CD38 antibody, or are triple-refractory. Lymphodepletion is administered (fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day)) daily on days -5 to -3, then CART-ddBCMA is given as a single infusion on day 0. Dose escalation was performed at 100 (DL1) and 300 (DL2) x 106 (+/- 20%) CAR+T cells and enrollment was continued at DL1 to further assess safety, efficacy, and pharmaco-kinetics and -dynamics. 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. MRD negative results were obtained by next-generation sequencing (Adaptive clonoSEQ).

Results: At the last data-cut performed on May 3, 2022, 37 patients (pts, median age 66 (range: 44-76)) were enrolled, 33 received CART-ddBCMA and 31 were evaluable for initial safety and clinical response. Median follow-up after CART-ddBCMA infusion was 12.1 months. 27 subjects received DL1 (6 in dose escalation and 21 in dose expansion, 25 evaluable) and 6 received DL2 (all evaluable). CAR+ cells comprised median 72% (48-87%) of total CD3+ T cells; median VCN was 2.2 copies/cell (1.1-3.5); median cell viability was 99% (91-100%), and median cell manufacturing yield was 1159 million cells (470-1626). Subjects had a median of 5 (3-16) prior lines of therapy. Twenty-four pts (77%) were “triple-refractory,” and 21 (68%) were “penta-refractory”; 12 pts (39%) had high tumor burden with ≥ 50% bone marrow plasma cells; and 12 (39%) pts (50%) had extramedullary disease at baseline. CRS was seen in 28/31 (90%) pts but only 1 subject (in DL2) had grade (G) 3 CRS and all other cases were G≤2. ICANS was seen in 7 subjects (5, G≤2; 2, G3), with 1 G3 case in each DL. All cases resolved without sequalae with standard management. No cases of off-tumor cell mediated toxicity, no delayed neurotoxicity events (i.e., occurring after day 28), and no Parkinsonian-like symptoms. All 31 evaluable subjects demonstrated clinical response per IMWG criteria (ORR, 100%) with 22 sCR/CR (≥CR rate, 71%), 7 VGPR (≥VGPR rate, 94%), and 2 PR. Responses deepened over time and conversion to CR/sCR was observed with longer follow-up (as late as month 12). Of those evaluable for MRD testing to date (n=22), 19 (86%) were MRD-neg at 10-5 or lower. Median duration of response, PFS & OS were not evaluable at the time of data-cut because 22 of 31 evaluable subjects (71%) had ongoing response. In the patients with ≥12 months follow-up (n=16), which included 8 (50%) patients with EMD, ORR was 100%, ≥CR rate was 81% (13/16) and ≥VGPR rate was 88% (14/16). CART-ddBCMA product characteristics were consistent with the specifications in all the lots and there were no manufacturing failures.

Conclusions: Adverse events including CRS and ICANS were manageable and no off-tumor tissue-targeted toxicity, delayed neurotoxicity, or Parkinsonian-like events were observed in the entire cohort. Ongoing efficacy results are encouraging, with 100% ORR, including 29 (94%) demonstrating deep clinical responses of ≥VGPR and 22 (71%) with CR/sCR. At the time of the meeting, updated data will be presented.

Disclosures: Frigault: JnJ/Legend: Consultancy; Iovance: Consultancy; Arcellx: Research Funding; Kite/Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Cytoagents: Consultancy; BMS: Consultancy. Rosenblatt: Wolters Kluwer Health Inc: Other: Spouse COI; Karyopharm Therapeutics: Other: DSMB; Dava Oncology: Other: Education; Celgene: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Attivare Therapeutics: Consultancy; Bioclinica: Consultancy; Imaging Endpoint: Consultancy; Parexel: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; BMS: Research Funding; Celgene: Research Funding; Kite: Honoraria. Dhakal: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Natera: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics: Honoraria, Speakers Bureau; BMS: Honoraria, Research Funding; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Raje: Medscape: Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Janssen: Consultancy, Honoraria. Cornwell: Arcellx: Current Employment. Banerjee: Arcellx: Current Employment. Rotte: Arcellx: Current Employment. Heery: Arcellx: Current Employment. Avigan: Sanofi: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexel: Consultancy; Takeda: Consultancy; Kite: Consultancy; Chugai: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Bio Tech: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd.: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kowa: Consultancy. Jakubowiak: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bishop: Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau; Agios: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; CRISPR Therapeutics: Consultancy, Research Funding; Iovance: Consultancy; Bluebird Bio: Consultancy; WindMIL Therapeutics: Consultancy; Arcellx: Consultancy, Research Funding; Autolus: Consultancy, Research Funding; Immatics: Research Funding; Triumvira: Research Funding; Tmunity: Research Funding; Chimeric Therapeutics: Consultancy; Sana Biotechnology: Consultancy; ADC Therapeutics: Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support , Research Funding; Sanofi: Honoraria, Speakers Bureau; Celgene: Honoraria; Incyte: Honoraria, Other: Travel support , Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Servier: Speakers Bureau.

*signifies non-member of ASH