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FIRST CLINICAL STUDY OF THE ANTI-SIGNAL REGULATORY PROTEIN-ALPHA (SIRPΑ) ANTIBODY CC-95251 COMBINED WITH RITUXIMAB IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) NON-HODGKIN LYMPHOMA (NHL)
Author(s): ,
Paolo Strati
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,États-unis;The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;The University of Texas MD Anderson Cancer Center,Houston,United States;The University of Texas MD Anderson Cancer Center,Houston,Estados Unidos;The University of Texas MD Anderson Can
,
Eliza Hawkes
Affiliations:
Austin Health–Austin Hospital,Heidelberg,Australie;Austin Health–Austin Hospital,Heidelberg,Australien;Austin Health–Austin Hospital,Heidelberg,Australia;Austin Health–Austin Hospital,Heidelberg,Australia;Austin Health–Austin Hospital,Heidelberg,Australia;Austin Health–Austin Hospital,Heidelberg,Australië;Austin Health–Austin Hospital,Heidelberg,Austrália;Austin Health–Austin Hospital,Heidelberg,А
,
Nilanjan Ghosh
Affiliations:
Levine Cancer Institute,Charlotte,États-unis;Levine Cancer Institute,Charlotte,Vereinigte Staaten;Levine Cancer Institute,Charlotte,Stati Uniti;Levine Cancer Institute,Charlotte,United States;Levine Cancer Institute,Charlotte,Estados Unidos;Levine Cancer Institute,Charlotte,Verenigde Staten;Levine Cancer Institute,Charlotte,Estados Unidos;Levine Cancer Institute,Charlotte,United States;Levine Canc
,
Joseph Tuscano
Affiliations:
University of California, Davis,Sacramento,États-unis;University of California, Davis,Sacramento,Vereinigte Staaten;University of California, Davis,Sacramento,Stati Uniti;University of California, Davis,Sacramento,United States;University of California, Davis,Sacramento,Estados Unidos;University of California, Davis,Sacramento,Verenigde Staten;University of California, Davis,Sacramento,Estados Uni
,
Quincy Chu
Affiliations:
Cross Cancer Institute,Edmonton,Canada;Cross Cancer Institute,Edmonton,Kanada;Cross Cancer Institute,Edmonton,Canada;Cross Cancer Institute,Edmonton,Canada;Cross Cancer Institute,Edmonton,Canadá;Cross Cancer Institute,Edmonton,Canada;Cross Cancer Institute,Edmonton,Canadá;Cross Cancer Institute,Edmonton,Канада;Cross Cancer Institute,Edmonton,Kanada
,
Marry Ann Anderson
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australie;Peter MacCallum Cancer Centre,Melbourne,Australien;Peter MacCallum Cancer Centre,Melbourne,Australia;Peter MacCallum Cancer Centre,Melbourne,Australia;Peter MacCallum Cancer Centre,Melbourne,Australia;Peter MacCallum Cancer Centre,Melbourne,Australië;Peter MacCallum Cancer Centre,Melbourne,Austrália;Peter MacCallum Cancer Centre,Melbourne,Австралия
,
Amar Patel
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Michael R. Burgess
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Kristen Hege
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Sapna Chhagan
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Sarandeep Boyanapalli
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Tracy Day
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
,
Frank Shen
Affiliations:
Bristol Myers Squibb,Princeton,États-unis;Bristol Myers Squibb,Princeton,Vereinigte Staaten;Bristol Myers Squibb,Princeton,Stati Uniti;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,Verenigde Staten;Bristol Myers Squibb,Princeton,Estados Unidos;Bristol Myers Squibb,Princeton,United States;Bristol Myers Squibb,Princeton,USA
Amitkumar Mehta
Affiliations:
University of Alabama at Birmingham,Birmingham,États-unis;University of Alabama at Birmingham,Birmingham,Vereinigte Staaten;University of Alabama at Birmingham,Birmingham,Stati Uniti;University of Alabama at Birmingham,Birmingham,United States;University of Alabama at Birmingham,Birmingham,Estados Unidos;University of Alabama at Birmingham,Birmingham,Verenigde Staten;University of Alabama at Birmi
(Abstract release date: 05/12/22) EHA Library. Strati P. 06/12/22; 357083; S219
Paolo Strati
Paolo Strati
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S219

Type: Oral Presentation

Session title: Aggressive Lymphoma - Novel agents

Background
CD47 is a cell-surface ligand overexpressed in various malignancies that binds to SIRPα on effector macrophages to promote tumor cell evasion of phagocytosis. Blockade of this CD47–SIRPα interaction enhances phagocytosis mediated by tumor-targeting antibodies, such as rituximab (ritux). Agents targeting CD47 combined with ritux have demonstrated promising clinical activity in R/R NHL; however, the broad expression of CD47 potentially acts as an antigen sink, reducing anti-tumor activity, and leads to on-target, off-tumor toxicities, including hemolytic anemia. CC-95251 is a novel, fully human immunoglobulin G1 antibody (Ab) that binds to SIRPα on macrophages to potently block the CD47–SIRPα interaction. 

Aims
The primary objectives of this multicenter, open-label, phase 1, dose-escalation and dose-expansion study were to evaluate the safety and tolerability of escalating doses of CC‑95251 + ritux and to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose for the combination in patients (pts) with CD20+ R/R NHL (NCT03783403). Here, we report interim results.

Methods
Pts were treated in 28-day cycles (C) with CC-95251 administered intravenously at doses of 3, 10, or 20 mg/kg every week (QW) and with ritux 375 mg/m2 on days (D) 1, 8, 15, and 22 of C1, D1 of C2–5, and D1 of every other cycle C6–24 until disease progression or unacceptable toxicity.

Results
As of 5 August 2021, 17 pts had received ≥ 1 dose of CC-95251 + ritux. Median age was 67 (range 30–84) years. Pts had received a median of 3 (range 1–7) prior systemic therapies, with 100% of pts having a prior history of anti-CD20 Ab exposure. Enrolled tumor types included R/R diffuse large B-cell lymphoma in 13 (77%) pts, follicular lymphoma in 2 (12%), and mantle cell lymphoma and marginal zone lymphoma in 1 (6%) pt each. Twelve (71%) pts had disease refractory to any prior line of therapy (LOT), including 10 (59%) refractory to any anti-CD20 Ab-containing regimen, and 9 (53%) to their last LOT. Pts received a median of 4 (range 1–14) cycles of CC-95251. Median duration of treatment was 16.4 (range 2.1–53.1) weeks. There was 1 CC-95251 dose reduction, and 6 (35%) pts experienced ≥ 1 treatment-emergent adverse event (TEAE) leading to CC-95251 dose interruption. MTD has not been reached. Neutropenia and infection were the most common TEAEs for any grade (71% and 59% respectively) and grade ≥ 3 (59% and 29% respectively). Treatment-related adverse events of grade ≥ 3 included neutropenia in 9 pts (53%) and infection in 2 pts (12%); no treatment-related anemia or deaths were reported. Overall response rate in the efficacy evaluable population was 56% (9/16), with 4 (25%) pts achieving a complete response (CR). Of 9 pts refractory to any prior anti-CD20 Ab-containing regimen, 2 pts achieved a CR and 2 pts had stable disease. Median time to response was 7.9 weeks. Duration of response ranged 7.4–28.1 weeks with a CR ongoing in 1 pt. In this dose-escalation study, CC-95251 demonstrated dose-proportional increases in exposure at doses > 3 mg/kg QW and full receptor occupancy at doses ≥ 3 mg/kg.

Conclusion
CC-95251 + ritux demonstrated a manageable safety profile and promising efficacy in pts with heavily pretreated CD20+ R/R NHL. The study is currently enrolling in the dose-expansion phase.

Keyword(s): Antibody targeting, Clinical trial, Immunotherapy, Non-Hodgkin's lymphoma

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S219

Type: Oral Presentation

Session title: Aggressive Lymphoma - Novel agents

Background
CD47 is a cell-surface ligand overexpressed in various malignancies that binds to SIRPα on effector macrophages to promote tumor cell evasion of phagocytosis. Blockade of this CD47–SIRPα interaction enhances phagocytosis mediated by tumor-targeting antibodies, such as rituximab (ritux). Agents targeting CD47 combined with ritux have demonstrated promising clinical activity in R/R NHL; however, the broad expression of CD47 potentially acts as an antigen sink, reducing anti-tumor activity, and leads to on-target, off-tumor toxicities, including hemolytic anemia. CC-95251 is a novel, fully human immunoglobulin G1 antibody (Ab) that binds to SIRPα on macrophages to potently block the CD47–SIRPα interaction. 

Aims
The primary objectives of this multicenter, open-label, phase 1, dose-escalation and dose-expansion study were to evaluate the safety and tolerability of escalating doses of CC‑95251 + ritux and to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose for the combination in patients (pts) with CD20+ R/R NHL (NCT03783403). Here, we report interim results.

Methods
Pts were treated in 28-day cycles (C) with CC-95251 administered intravenously at doses of 3, 10, or 20 mg/kg every week (QW) and with ritux 375 mg/m2 on days (D) 1, 8, 15, and 22 of C1, D1 of C2–5, and D1 of every other cycle C6–24 until disease progression or unacceptable toxicity.

Results
As of 5 August 2021, 17 pts had received ≥ 1 dose of CC-95251 + ritux. Median age was 67 (range 30–84) years. Pts had received a median of 3 (range 1–7) prior systemic therapies, with 100% of pts having a prior history of anti-CD20 Ab exposure. Enrolled tumor types included R/R diffuse large B-cell lymphoma in 13 (77%) pts, follicular lymphoma in 2 (12%), and mantle cell lymphoma and marginal zone lymphoma in 1 (6%) pt each. Twelve (71%) pts had disease refractory to any prior line of therapy (LOT), including 10 (59%) refractory to any anti-CD20 Ab-containing regimen, and 9 (53%) to their last LOT. Pts received a median of 4 (range 1–14) cycles of CC-95251. Median duration of treatment was 16.4 (range 2.1–53.1) weeks. There was 1 CC-95251 dose reduction, and 6 (35%) pts experienced ≥ 1 treatment-emergent adverse event (TEAE) leading to CC-95251 dose interruption. MTD has not been reached. Neutropenia and infection were the most common TEAEs for any grade (71% and 59% respectively) and grade ≥ 3 (59% and 29% respectively). Treatment-related adverse events of grade ≥ 3 included neutropenia in 9 pts (53%) and infection in 2 pts (12%); no treatment-related anemia or deaths were reported. Overall response rate in the efficacy evaluable population was 56% (9/16), with 4 (25%) pts achieving a complete response (CR). Of 9 pts refractory to any prior anti-CD20 Ab-containing regimen, 2 pts achieved a CR and 2 pts had stable disease. Median time to response was 7.9 weeks. Duration of response ranged 7.4–28.1 weeks with a CR ongoing in 1 pt. In this dose-escalation study, CC-95251 demonstrated dose-proportional increases in exposure at doses > 3 mg/kg QW and full receptor occupancy at doses ≥ 3 mg/kg.

Conclusion
CC-95251 + ritux demonstrated a manageable safety profile and promising efficacy in pts with heavily pretreated CD20+ R/R NHL. The study is currently enrolling in the dose-expansion phase.

Keyword(s): Antibody targeting, Clinical trial, Immunotherapy, Non-Hodgkin's lymphoma

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