Kristen Hege, MD – Bristol Myers Squibb discusses Phase 1 proof-of-concept data (via an oral presentation) on novel CELMoD CC-92480 from ASCO 2020.
Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed to allow Ikaros and Aiolos to degrade quickly and maximally. In vitro, it has increased antiproliferative and tumoricidal activity with high immune stimulating activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM).
Methods: Phase 1, multicenter, maximum tolerated dose (MTD) dose escalation analysis, suggested phase 2 dose, protection, tolerability, and pharmacokinetics of CC-92480 + DEX in highly pretreated RRMM pts. On or within 60 days of their last MM treatment, qualifying pts had development and were either resistant to or intolerant to, or not otherwise candidate for, currently available therapies. The escalating doses of CC-92480 + DEX (40 mg; 20 mg if ⇠75 yrs) were evaluated in several treatment schedules.
Results: 66 pts had earned CC-92480 + DEX as of 24 Dec 2019. Average age was 67 yrs (range 40"“78), average number of previous regimens was 6 (range 2"“13). Previous therapies included transplantation of stem cells (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). 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) were included in the CC-92480 doses examined. For both 10/14 average 2 and 21/28 schedules, MTD was 1.0 mg. In 58 (88 percent) pts, Grade 3"“4 treatment-emergent adverse effects (TEAEs) were recorded. Neutropenia (53 percent), infections (30 percent), anemia (29 percent), and thrombocytopenia (17 percent), with 9 percent grade 3 fatigue, were the most common grade 3-4 TEAEs. 10 pts had dose-limiting toxicity (the majority linked to neutropenia) across various cohorts. The overall response rate (ORR) for the efficacy assessable population (n = 66) was 21 per cent (9 very strong partial responses [VGPRs]; 5 PRs). Efficacy was dose-dependent and schedule-dependent; 10 of 21 (48 percent) pts (7 VGPR and 3 PR) responded in two 1.0 mg QD schedules (10/14 a.m. 2 and 21/28) with an individual response to immunomodulatory drug (IMiD) refractory. Increase in plasma exposure and peripheral degradation of Ikaros blood and Aiolos is dose-dependent. In LEN- and POM-refractory pts, Ikaros and Aiolos decreased significantly in the bone marrow plasma cells. Conclusions: TEAEs of CC-92480 were predominantly associated with highly pretreated myelosuppression, including triple-class-refractory, RRMM pts. Promising activity was observed at therapeutic doses of 48 percent ORR. In order to further refine the dosage and schedule, the research is continuing, with combination trials underway and cohorts for dosage expansion expected. Data on clinical trials: NCT03374085.