INTERIM RESULTS FROM THE FIRST PHASE 1 CLINICAL STUDY OF THE B-CELL MATURATION ANTIGEN (BCMA) 2+1 T CELL ENGAGER (TCE) CC-93269 IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)
Author(s): ,
Luciano J. Costa
Affiliations:
Division of Hematology and Oncology,University of Alabama at Birmingham,Birmingham,United States
,
Sandy W. Wong
Affiliations:
Department of Medicine,University of California,San Francisco,United States
,
Arancha Bermúdez
Affiliations:
Hematology Service,University Hospital Marqués de Valdecilla (IDIVAL),Santander,Spain
,
Javier de la Rubia
Affiliations:
Hematology Service,University Hospital Doctor Peset,Valencia,Spain
,
María Victoria Mateos
Affiliations:
Institute of Cancer Molecular and Cellular Biology,University Hospital of Salamanca,Salamanca,Spain
,
Enrique M. Ocio
Affiliations:
Hematology Service,University Hospital Marqués de Valdecilla (IDIVAL),Santander,Spain
,
Paula Rodríguez-Otero
Affiliations:
Department of Hematology,Clínica Universidad de Navarra, Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Jesús San Miguel
Affiliations:
Department of Hematology,Clínica Universidad de Navarra, Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Shaoyi Li
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Rafael Sarmiento
Affiliations:
Celgene Institute for Translational Research Europe, a Bristol-Myers Squibb Company,Seville,Spain
,
Pilar Lardelli
Affiliations:
Celgene Institute for Translational Research Europe, a Bristol-Myers Squibb Company,Seville,Spain
,
Allison Gaudy
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Isaac Boss
Affiliations:
Bristol-Myers Squibb,Seattle,United States
,
Lisa M. Kelly
Affiliations:
Bristol-Myers Squibb,San Francisco,United States
,
Michael R. Burgess
Affiliations:
Bristol-Myers Squibb,San Francisco,United States
,
Kristen Hege
Affiliations:
Bristol-Myers Squibb,San Francisco,United States
William I. Bensinger
Affiliations:
Myeloma and Transplant Program,Swedish Cancer Institute,Seattle,United States
EHA Library. J. Costa L. 06/12/20; 295025; S205
Luciano J. Costa
Luciano J. Costa
Contributions
Abstract

Abstract: S205

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Management of relapsed/refractory multiple myeloma and minimal residual disease assessment

Background
CC-93269 is an asymmetric 2-arm humanized IgG1 TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format. The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking, which leads to T cell activation, resulting in myeloma cell death.

Aims
This phase 1 dose-finding study (NCT03486067) was conducted to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D) in pts with RRMM.

Methods
Eligible pts had received ≥3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on day (D) 1, 8, 15, and 22 for cycles (C) 1–3; D1 and 15 for C4–6; and on D1 for C7 and beyond, all in 28-day cycles for up to 2 years. Dose escalation involved 2 stages: stage 1, CC-93269 given in fixed doses; stage 2, a fixed first dose on C1D1, followed by intrapatient dose escalation on C1D8.

Results
As of October 28, 2019, 30 pts had received CC-93269. Median age was 64 years (range 42–78), with a median of 5.9 years (range 1.4–16.6) since initial diagnosis. Median number of prior regimens was 5 (range 3–13) and included treatment with autologous stem cell transplantation (SCT) (77%), allogeneic SCT (10%), lenalidomide (100%), pomalidomide (87%), bortezomib (100%), carfilzomib (77%), and daratumumab (DARA; 93%). All pts had MM refractory to their last line of therapy, with 23 (77%) refractory to DARA, 23 (77%) to last proteasome inhibitor, and 24 (80%) to last immunomodulatory agent.

CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.0 weeks (range 1.6–46.0) with pts receiving a median of 3.5 cycles (range 1–12). Grade 3–4 treatment-emergent adverse events were reported in 22 (73%) pts; those occurring in ≥2 pts included neutropenia (43%), anemia (37%), infections (30%), thrombocytopenia (17%), general physical health deterioration (10%), and pyrexia (7%). Cytokine release syndrome (CRS) was reported in 23 (77%) pts, the majority of whom reported a maximum grade 1 (n=15 [50%]) or grade 2 (n=7 [23%]), and occurred most frequently with the first or second dose (n=30 of 37 events [81%]). CRS prophylaxis was implemented with dexamethasone (DEX) for first dose and dose increases in pts receiving ≥6 mg. 22 (73%) pts received DEX and 13 (43%) pts received tocilizumab for the management of CRS. One pt receiving 6 mg CC-93269 as first dose and 10 mg on C1D8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity was observed, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines.

Overall, 13 pts achieved a partial response or better (overall response rate [ORR]; 43%), including 5 (17%) with a complete response (CR) or stringent CR (sCR). Among 9 pts receiving 10 mg, the ORR was 89%, including 44% sCR/CR (Table). Of the 13 responders, 92% achieved minimal residual disease (MRD) negativity (≤1/105) in the bone marrow on or before C4D1 by Euroflow. The median time to response was 4.1 weeks (range 4.0–13.1), and 11 responses were ongoing with duration of response ranging from 5.3 to 40.6 weeks. The NTD, MTD, and RP2D have not yet been reached.

Conclusion
CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose-escalation phase.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Antibody, Immunotherapy, Multiple myeloma

Abstract: S205

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Management of relapsed/refractory multiple myeloma and minimal residual disease assessment

Background
CC-93269 is an asymmetric 2-arm humanized IgG1 TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format. The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking, which leads to T cell activation, resulting in myeloma cell death.

Aims
This phase 1 dose-finding study (NCT03486067) was conducted to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D) in pts with RRMM.

Methods
Eligible pts had received ≥3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on day (D) 1, 8, 15, and 22 for cycles (C) 1–3; D1 and 15 for C4–6; and on D1 for C7 and beyond, all in 28-day cycles for up to 2 years. Dose escalation involved 2 stages: stage 1, CC-93269 given in fixed doses; stage 2, a fixed first dose on C1D1, followed by intrapatient dose escalation on C1D8.

Results
As of October 28, 2019, 30 pts had received CC-93269. Median age was 64 years (range 42–78), with a median of 5.9 years (range 1.4–16.6) since initial diagnosis. Median number of prior regimens was 5 (range 3–13) and included treatment with autologous stem cell transplantation (SCT) (77%), allogeneic SCT (10%), lenalidomide (100%), pomalidomide (87%), bortezomib (100%), carfilzomib (77%), and daratumumab (DARA; 93%). All pts had MM refractory to their last line of therapy, with 23 (77%) refractory to DARA, 23 (77%) to last proteasome inhibitor, and 24 (80%) to last immunomodulatory agent.

CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.0 weeks (range 1.6–46.0) with pts receiving a median of 3.5 cycles (range 1–12). Grade 3–4 treatment-emergent adverse events were reported in 22 (73%) pts; those occurring in ≥2 pts included neutropenia (43%), anemia (37%), infections (30%), thrombocytopenia (17%), general physical health deterioration (10%), and pyrexia (7%). Cytokine release syndrome (CRS) was reported in 23 (77%) pts, the majority of whom reported a maximum grade 1 (n=15 [50%]) or grade 2 (n=7 [23%]), and occurred most frequently with the first or second dose (n=30 of 37 events [81%]). CRS prophylaxis was implemented with dexamethasone (DEX) for first dose and dose increases in pts receiving ≥6 mg. 22 (73%) pts received DEX and 13 (43%) pts received tocilizumab for the management of CRS. One pt receiving 6 mg CC-93269 as first dose and 10 mg on C1D8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity was observed, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines.

Overall, 13 pts achieved a partial response or better (overall response rate [ORR]; 43%), including 5 (17%) with a complete response (CR) or stringent CR (sCR). Among 9 pts receiving 10 mg, the ORR was 89%, including 44% sCR/CR (Table). Of the 13 responders, 92% achieved minimal residual disease (MRD) negativity (≤1/105) in the bone marrow on or before C4D1 by Euroflow. The median time to response was 4.1 weeks (range 4.0–13.1), and 11 responses were ongoing with duration of response ranging from 5.3 to 40.6 weeks. The NTD, MTD, and RP2D have not yet been reached.

Conclusion
CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose-escalation phase.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Antibody, Immunotherapy, Multiple myeloma

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