FIRST-IN-HUMAN PHASE 1 STUDY OF THE NOVEL CELMOD AGENT CC-92480 COMBINED WITH DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
Author(s): ,
Paul G. Richardson
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Annette J. Vangsted
Affiliations:
Department of Haematology,Rigshospitalet,Copenhagen,Denmark
,
Karthik Ramasamy
Affiliations:
Department of Clinical Haematology,Oxford University Hospitals NHS Foundation Trust,Oxford,United Kingdom
,
Suzanne Trudel
Affiliations:
Division of Medical Oncology and Hematology,Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada
,
Joaquín Martínez
Affiliations:
Department of Hematology,Hospital 12 de Octubre, Complutense University, H12O-CNIO Clinical Research Unit, CIBERONC,Madrid,Spain
,
María-Victoria Mateos
Affiliations:
University Hospital of Salamanca/IBSAL,Salamanca,Spain
,
Paula Rodríguez-Otero
Affiliations:
Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC,Pamplona,Spain
,
Sagar Lonial
Affiliations:
Winship Cancer Institute,Emory University,Atlanta,United States
,
Rakesh Popat
Affiliations:
NIHR UCLH Clinical Research Facility,University College London Hospitals NHS Foundation Trust,London,United Kingdom
,
Albert Oriol
Affiliations:
Institut Català d'Oncologia and Institut Josep Carreras,Hospital Germans Trias i Pujol,Badalona,Spain
,
Chatchada Karanes
Affiliations:
Judy and Bernard Briskin Center for Multiple Myeloma Research,City of Hope,Duarte,United States
,
Robert Z. Orlowski
Affiliations:
Department of Lymphoma & Myeloma,The University of Texas MD Anderson Cancer Center,Houston,United States
,
Jesus G. Berdeja
Affiliations:
Sarah Cannon Center for Blood Cancers,Nashville,United States
,
Pekka Anttila
Affiliations:
Hematology,University of Helsinki and Helsinki University Hospital,Helsinki,Finland
,
Martin Kaiser
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
C. Ola Landgren
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Lilly Wong
Affiliations:
Bristol-Myers Squibb,San Diego,United States
,
Chenyang Shi
Affiliations:
Bristol-Myers Squibb,Berkeley Heights,United States
,
Manisha Lamba
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Evelyn Barnett
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Alix Harding
Affiliations:
Celgene Research SLU, A Bristol-Myers Squibb Company,Seville,Spain
,
Zariana Nikolova
Affiliations:
Celgene International, A Bristol-Myers Squibb Company,Boudry,Switzerland
,
Daniel W. Pierce
Affiliations:
Bristol-Myers Squibb,San Francisco,United States
,
Michael Pourdehnad
Affiliations:
Bristol-Myers Squibb,San Francisco,United States
Nizar J. Bahlis
Affiliations:
Arnie Charbonneau Cancer Institute,University of Calgary,Calgary,Canada
EHA Library. Richardson P. 06/12/20; 295028; S208
Dr. Paul Richardson
Dr. Paul Richardson
Contributions
Abstract

Abstract: S208

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-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in multiple myeloma (MM) cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity.

Aims
This phase 1, multicenter, dose-escalation study (NCT03374085) evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + dexamethasone (DEX) in heavily pretreated patients with relapsed/refractory MM (RRMM).

Methods
Eligible patients had disease progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for, currently available therapies. Several treatment schedules evaluated escalating doses of CC-92480 + DEX (40 mg, or 20 mg if ≥ 75 years of age).

Results
As of December 24, 2019, 66 patients had received CC-92480 + DEX. Median age was 67 years (range 40–78), and median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses and schedules explored included 0.1–1.0 mg once daily (QD) (10/14 days), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg twice daily (3/14 days), and 1.6–2.0 mg QD (7/14 days). The MTD was 1.0 mg for both 10/14 days and 21/28 days schedules.

Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) patients. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among the different cohorts, 10 patients had dose-limiting toxicities, the majority of which were related to neutropenia.

The overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 partial responses [PRs]). Efficacy was dose- and schedule-dependent; across two 1.0 mg QD schedules (10/14 days and 21/28 days), 10 of 21 (48%) patients responded (7 VGPRs and 3 PRs), with response independent of refractoriness to prior immunomodulatory drugs (IMiDs).

Plasma exposure and peripheral blood Ikaros and Aiolos degradation were dose-dependent. CC-92480 significantly decreased Ikaros and Aiolos in bone marrow plasma cells, including those of LEN- and POM-refractory patients.

Conclusion
TEAEs associated with CC-92480 were related mainly to myelosuppression in heavily pretreated, including triple-class-refractory (refractory to at least one IMiD drug, one proteasome inhibitor, and one anti-CD38 antibody), patients with RRMM. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize the dose and schedule, with combination studies underway and dose-expansion cohorts planned.

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

Keyword(s): Ikaros, Multiple myeloma, Phase I/II, Refractory

Abstract: S208

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-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in multiple myeloma (MM) cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity.

Aims
This phase 1, multicenter, dose-escalation study (NCT03374085) evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + dexamethasone (DEX) in heavily pretreated patients with relapsed/refractory MM (RRMM).

Methods
Eligible patients had disease progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for, currently available therapies. Several treatment schedules evaluated escalating doses of CC-92480 + DEX (40 mg, or 20 mg if ≥ 75 years of age).

Results
As of December 24, 2019, 66 patients had received CC-92480 + DEX. Median age was 67 years (range 40–78), and median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses and schedules explored included 0.1–1.0 mg once daily (QD) (10/14 days), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg twice daily (3/14 days), and 1.6–2.0 mg QD (7/14 days). The MTD was 1.0 mg for both 10/14 days and 21/28 days schedules.

Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) patients. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among the different cohorts, 10 patients had dose-limiting toxicities, the majority of which were related to neutropenia.

The overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 partial responses [PRs]). Efficacy was dose- and schedule-dependent; across two 1.0 mg QD schedules (10/14 days and 21/28 days), 10 of 21 (48%) patients responded (7 VGPRs and 3 PRs), with response independent of refractoriness to prior immunomodulatory drugs (IMiDs).

Plasma exposure and peripheral blood Ikaros and Aiolos degradation were dose-dependent. CC-92480 significantly decreased Ikaros and Aiolos in bone marrow plasma cells, including those of LEN- and POM-refractory patients.

Conclusion
TEAEs associated with CC-92480 were related mainly to myelosuppression in heavily pretreated, including triple-class-refractory (refractory to at least one IMiD drug, one proteasome inhibitor, and one anti-CD38 antibody), patients with RRMM. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize the dose and schedule, with combination studies underway and dose-expansion cohorts planned.

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

Keyword(s): Ikaros, Multiple myeloma, Phase I/II, Refractory

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