First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Bibliographic record
Abstract
8500 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 .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".