Authors: Paul G. Richardson, Annette J. Vangsted, Karthik Ramasamy, Suzanne Trudel, Joaquín Martínez, Maria-Victoria Mateos, Paula Rodríguez Otero, Sagar Lonial, Rakesh Popat, Albert Oriol, Chatchada Karanes, Robert Z. Orlowski, Jesus G. Berdeja, Lilly Wong, Chenyang Shi, Manisha Lamba, Evelyn Barnett, Daniel W. Pierce, Michael Pourdehnad, Nizar J. Bahlis; Dana-Farber Cancer Institute, Boston, MA; Department of Haematology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Department of Hematology, Hospital 12 de Octubre, Complutense University, H12O-CNIO Clinical Research Unit, CIBERONC, Madrid, Spain; University Hospital of Salamanca/IBSAL, Salamanca, Spain; University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain; Winship Cancer Institute, Emory University, Atlanta, GA; NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain; Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; Sarah Cannon Center for Blood Cancers, Nashville, TN; Bristol-Myers Squibb, San Diego, CA; Bristol-Myers Squibb, Berkley Heights, NJ; Bristol-Myers Squibb, Summit, NJ; Bristol-Myers Squibb, San Francisco, CA; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
Research Funding: Bristol-Myers Squibb
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 MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity.
Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had 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 tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs).
Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), 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 explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts.
Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085.