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577 Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novelty in CAR T in Relapsed/Refractory Multiple Myeloma
Hematology Disease Topics & Pathways:
Diseases, Biological, Adult, multiple myeloma, Therapies, CAR-Ts, white blood cells, Cell Lineage, Plasma Cell Disorders, Study Population, Lymphoid Malignancies, Clinically relevant
Monday, December 9, 2019: 7:00 AM
Hall D, Level 2 (Orange County Convention Center)

Deepu Madduri, MD1*, Saad Z. Usmani, MD2, Sundar Jagannath3*, Indrajeet Singh, PhD4*, Enrique Zudaire, PhD4*, Tzu-Min Yeh5*, Alicia J. Allred, PhD4*, Arnob Banerjee, MD4*, Jenna D. Goldberg, MD5*, Jordan M Schecter, MD5, Sen Zhuang5*, Jeffrey R. Infante, MD4*, Syed Rizvi6*, Xiaohu (Frank) Fan, MD, PhD6*, Andrzej Jakubowiak, MD, PhD7 and Jesus G. Berdeja, MD8

1Icahn School of Medicine at Mount Sinai, New York, NY
2Levine Cancer Institute, Atrium Health, Charlotte, NC
3Mount Sinai Medical Center, New York, NY
4Janssen R&D, Spring House, PA
5Janssen R&D, Raritan, NJ
6Legend Biotech USA, Piscataway, NJ
7University of Chicago, Chicago, IL
8Sarah Cannon Research Institute, Nashville, TN

JNJ-68284528 (JNJ-4528) is a chimeric antigen receptor T cell (CAR-T) therapy containing two BCMA-targeting single-domain antibodies designed to confer avidity. A first-in-human phase 1 study (LEGEND-2) conducted in China of LCAR-B38M, an identical CAR to JNJ-4528, showed high overall response and manageable safety in 74 patients (pts) with R/R MM. Phase 1b results from the ongoing CARTITUDE-1 study conducted in the US with JNJ-4528 are presented here (NCT03548207).

Eligible pts (≥18 years) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria, had measurable disease as assessed by M-protein or serum free light chain levels, received ≥3 prior regimens or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and received an anti-CD38 antibody. Bridging therapy was allowed after apheresis. Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days were used as the conditioning regimen. A single infusion of JNJ-4528 at the targeted 0.75x106 CAR+ cells/kg (target range 0.5–1.0x106) dose was administered 5–7 days after the start of the conditioning regimen. Primary objectives for phase 1b were to characterize the safety of JNJ-4528 and confirm the recommended phase 2 dose (RP2D).

Adverse events (AEs) were graded using CTCAE, v5.0, cytokine release syndrome (CRS) using Lee et al. (Blood 2014;124:188), and neurotoxicity using both CTCAE, v5.0 and the ASTCT grading system (Lee et al. Biol Blood Marrow Transplant 2019 25(4):625). Response was assessed per IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry and/or next generation sequencing.

As of 24 Jun 2019, 25 pts had been infused with JNJ-4528 in the phase 1b portion of the study. Median age was 61 years (range 50–75), pts had received a median of 5 (range 3–16) prior lines of treatment, 88% were triple-refractory to a PI, IMiD, and anti-CD38 antibody, 72% were penta-exposed, and 36% were penta-refractory. The median administered dose was 0.73x106 CAR+ cells/kg (range 0.5–0.9x106).

Most frequently reported AEs were CRS (88%), neutropenia (80%), anemia (76%), and thrombocytopenia (72%). Hematologic AEs of grade ≥3 included neutropenia (76%), thrombocytopenia (60%), and anemia (48%). The majority of pts (80%) had grade 1–2 CRS, with 1 grade 3 event and 1 grade 5 event at day 99 from sequalae of grade 4 CRS (dose-limiting toxicity).

CRS events had a generally predictable time to onset, occurring at a median of 7 days (range 2–12) post-infusion with a median duration of 4 days (range 1–60). Tocilizumab and corticosteroids were administered in 91% and 27% of pts with CRS (n=22), respectively. Three pts had CAR-T-related neurotoxicity of grade 1 (n=2) and grade 3 (n=1); all events occurred in the context of CRS and resolved within 1–2 days.

At data cut-off, 21 pts were evaluable for response (postbaseline evaluation at day 28) with a median follow-up of 3 months (range 1–10). Reduction in tumor burden was observed for all pts (Figure). An overall response rate of 91% was observed, with 4 stringent complete responses (sCRs), 2 CRs, 7 very good partial responses, and 6 partial responses. Of the 15 pts with post-infusion day 28 evaluable bone marrow (BM) samples, 10 were MRD-negative at the 10-5 sensitivity level, 2 at the 10-4 sensitivity level, and 3 had unidentified clones. No pts had progressed at the time of data cutoff. Responses were independent of baseline BCMA expression.

JNJ-4528 CAR+ cellular and transgene levels showed expansion and persistence in both blood and BM, with peak expansion 9–14 days after dosing in a majority of pts. All pts showed similar kinetics of decline in soluble BCMA (sBCMA) levels, and continued depletion in sBCMA suggests CAR-T-mediated pharmacodynamic activity. Serum cytokine levels (i.e., IL-6, IFNγ, IL-10) increased post-infusion and peaked around day 10, coinciding with peak expansion of CAR+ T cells. Increases in some proinflammatory cytokines (i.e., IL-6) correlated with onset of CRS symptoms.

Collectively these results demonstrate that JNJ-4528 at a target dose of 0.75x106 CAR+ cells/kg delivers early and deep responses, including MRD negativity in all evaluable pts tested, with a manageable safety profile in pts with refractory MM. The safety and efficacy results from the ongoing CARTITUDE-1 study are consistent with the LEGEND-2 study and confirm the 0.75x106 CAR+ cells/kg dose as the RP2D for further clinical development.

Disclosures: Madduri: AbbVie: Consultancy; Foundation Medicine: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Usmani: Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Jagannath: AbbVie: Consultancy; Karyopharm Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Merck & Co.: Consultancy. Singh: Janssen R&D: Employment, Equity Ownership. Zudaire: Janssen R&D: Employment, Equity Ownership. Yeh: Janssen R&D: Employment, Equity Ownership. Allred: Janssen R&D: Employment, Equity Ownership. Banerjee: Janssen R&D: Employment, Equity Ownership. Goldberg: Janssen R&D: Employment, Equity Ownership. Schecter: Janssen R&D, LLC: Employment, Equity Ownership. Zhuang: Janssen R&D: Employment, Equity Ownership. Infante: Janssen R&D: Employment, Equity Ownership. Rizvi: Legend Biotech: Employment, Equity Ownership. Fan: Legend Biotech: Employment, Equity Ownership. Jakubowiak: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding.

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