Pharmacodynamic (Pd) Responses Drive Dose/Schedule Selection Of Cc-92480, A Novel Celmod Agent, In A Phase 1 Dose-Escalation Study In Relapsed/Refractory Multiple Myeloma (Rrmm).

8531 Background: CC-92480 is a novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a first-in-human phase 1 study (NCT03374085) in RRMM patients (pts). In preclinical studies, CC-92480 demonstrated efficient and sustained degradation of Ikaros/Aiolos leading to broad antiproliferative effects and induction of apoptosis in MM cell lines, and enhanced immune stimulatory effects. Methods: Eligible RRMM pts received escalating doses of CC-92480 + dexamethasone. Several dosing schedules were evaluated in parallel; more continuous with 4-day or 7-day breaks and intensive with longer breaks in a 28-day cycle. Peripheral blood and bone marrow aspirates (BMA) were taken before and during treatment at multiple time points. Levels of Ikaros/Aiolos in T cells, and effects on immunomodulation were assessed by flow cytometry. Weekly levels of free light chain (sFLC) and B-cell maturation antigen (sBCMA) were determined in serum during the first 2 cycles of treatment. BMA clots were analyzed by immunohistochemistry for CRBN, Ikaros, Aiolos, ZFP91, c-Myc, and IRF-4. Results: The rate and depth of Ikaros/Aiolos degradation in T cells increased with dose and reached maximal at ≥0.6 mg QD with sustained degradation over 24 hrs. Substrate recovery occurred during drug holidays with faster recovery at lower doses, and reached full recovery with ≥7-day break for all dose levels tested. B cells decreased with increasing dose, and T-cell proliferation was demonstrated at all doses/schedules. Substrate degradation was also evident in bone marrow plasma cells including in the setting of low CRBN levels. In these heavily pretreated, including triple-class-refractory, RRMM pts, CC-92480 dosing periods led to rapid and sustained decreases in sFLC and sBCMA. This was dose and schedule dependent and correlated with plasma exposure; the longer breaks in the intensive schedules led to rapid rebound of these markers, while the more continuous schedules maintained the depth of suppression. Conclusions: PD responses correlated with dose and schedule. PD samplings at multiple time points during treatment allowed dynamic changes and kinetics of each biomarker in all schedules to be followed and to inform next steps. Ikaros/Aiolos degradation and recovery, coupled with changes in sFLC and sBCMA, guided the adjustment of the dosing schedule during dose escalation in order to optimize efficacy and tolerability. The study is ongoing and selection of the recommended phase 2 dose is pending.