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651 Universal Updated Phase 1 Data Validates the Feasibility of Allogeneic Anti-BCMA ALLO-715 Therapy for Relapsed/Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Allogeneic CARs and CARs for T Cell Lymphomas
Hematology Disease Topics & Pathways:
Cytokine Release Syndrome, Clinical Trials, Biological, Adults, Neurotoxicity, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Immunology, Cell Expansion, Diseases, Therapies, Adverse Events, Gene Editing, Myeloid Malignancies, Biological Processes, Technology and Procedures, Study Population
Monday, December 13, 2021: 11:00 AM

Sham Mailankody, MBBS 1, Michaela Liedtke, MD2, Surbhi Sidana, MD3, Jeffrey V. Matous, MD4, Saurabh Chhabra, MD, MS5, Olalekan O. Oluwole, MBBS, MPH6, Shahbaz A. Malik, MD7, Shaji K Kumar, MD8, Rajneesh Nath, MD9, Faiz Anwer, MD10, Jose Carlos Cruz, MD11, Sundar Jagannath12, Myo Htut13, Noopur S. Raje, MD14, David S. Siegel, MD, PhD15, Erin E. Karski, MD16*, Wade Lovelace16*, Afrodite Lourbakos, PhD16*, Srinand Ponnathapura Nandakumar, PhD16*, Arun Balakumaran, MD, PhD16 and Parameswaran Hari5

1Myeloma Service and Cellular Therapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Division of Hematology, Department of Medicine, Stanford University, Stanford, CA
3Division of BMT and Cell Therapy, Stanford University Hospital, Stanford, CA
4Colorado Blood Cancer Institute, Denver, CO
5Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
6Vanderbilt University Medical Center, Nashville, TN
7Bone Marrow Transplant and Cellular Therapy Program, Sarah Cannon Blood Cancer Center at St. David's South Austin Medical Center, Austin, TX
8Mayo Clinic, Rochester, MN
9Banner MD Anderson Cancer Center, Gilbert, AZ
10Taussig Cancer Institute, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH
11Texas Transplant Institute, San Antonio, TX
12Department of Medicine, Hematology and Medical Oncology, Mount Sinai Medical Center, New York, NY
13Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA
14Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA
15John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
16Allogene Therapeutics, South San Francisco, CA

Background

Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR T™ cell which uses Cellectis TALEN® technology to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD).

Methods

UNIVERSAL is an open-label, Phase 1 trial (NCT04093596) in adults with relapsed/refractory (R/R) multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Pts receive LD followed by ALLO-715 at 1 of 4 dose levels (DLs) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated: FCA39; FCA60; FCA90; and CA39; with fludarabine [F] 90 mg/m2, cyclophosphamide [C] 900 mg/m2, and ALLO-647 [A] 39, 60, or 90 mg divided over 3 days.

Results

As of June 21, 2021 data-cut, 47 subjects were enrolled; 42 were treated with ALLO-715; 5 progressed prior to treatment. Median time from enrollment to LD was 5 days and no treated pts required bridging therapy. Pts were heavily pretreated with a range of 3-11 prior lines of therapy; 42.9% were penta refractory. There were 19% ISS Stage III at screening, 34% had high risk cytogenetics, and 19% had extramedullary disease. The most common Grade (Gr) 3+ adverse events (AEs) included anemia, neutropenia, lymphopenia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 52.4%, all Gr 1/2 except 1 pt with Gr 3. CRS was treated with tocilizumab (21.3%) and corticosteroids (12.8%). One pt (with Gr 2 CRS) experienced Gr 1 neurotoxicity that resolved. Gr 3+ infections occurred in 12.8% of pts, including 2 previously reported Gr 5 events (fungal pneumonia and adenovirus hepatitis).

Early results from this trial have been presented previously (ASH 2020) and therefore the efficacy analysis on pts (n=26) treated at DL3 and DL4 with FCA LD, which are considered a more relevant cell dose and LD, is presented here (Table). In pts who received DL3 or DL4 (320 or 480 x 106 CAR T cells) (n=26), the ORR was 61.5% (95% CI: 40.6, 79.8); very good partial response or better (VGPR+) rate was 38.5% (95% CI: 20.2, 59.4). Median time to 1st response was 16 days. The median follow-up for the DL3/DL4 pts was 7.4 months (95% CI: 3.6, 9.9) with a median duration of response of 8.3 months (95% CI: 1.5, not reached). Of the 10 pts with a best response of VGPR+, 8 were found to be negative by minimal residual disease (MRD) analysis.

Conclusions

UNIVERSAL demonstrates proof of concept for allogeneic CAR T therapy in multiple myeloma. ALLO-715 showed CAR T cell dose response relationship with higher doses (DL3/DL4) leading to clinically meaningful efficacy, including high VGPR+ rate of 38.5% and high MRD negativity without requiring leukapheresis or bridging therapy. ALLO-715 following LD with FCA has a tolerable safety profile. FCA induces a deep and durable window of lymphocyte depletion allowing CAR T cell expansion and persistence. A study using the next generation anti-BCMA CAR (ALLO-605) which supplies cytokine signaling to the CAR bearing cells is ongoing (IGNITE). The current UNIVERSAL trial continues to enroll, including a cohort with consolidation, and updated data will be presented at the meeting.

Disclosures: Mailankody: Allogene Therapeutics: Research Funding; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy; Takeda Oncology: Research Funding. Liedtke: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Sidana: BMS: Consultancy; Magenta Therapeutics: Consultancy, Research Funding; Allogene: Research Funding; Janssen: Consultancy, Research Funding. Chhabra: GSK: Honoraria. Oluwole: Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Kumar: Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Anwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding. Raje: Amgen: Other; bluebird bio: Other; Janssen: Other; Caribou: Other; BMS: Other; Celgene: Other. Siegel: Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Karski: Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Crispr Therapeutics: Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company. Lovelace: Allogene Therapeutics, Inc.: Current Employment. Lourbakos: Allogene Therapeutics, Inc.: Current Employment. Hari: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.

*signifies non-member of ASH