Results from a first-in-human trial of CC-92480 in patients with relapsed or refractory multiple myeloma show a manageable safety profile and promising efficacy, according to findings presented by Paul G. Richardson, MD, of Dana-Faber Cancer Institute in Boston, at EHA25 Virtual, the 25th European Hematology Association Congress.
“CC-92480 is a novel CEreblon E3 Ligase MoDulator, or CELMoD agent, designed for the rapid, maximal degradation of the target proteins Ikaros and Aiolos,” Dr. Richardson explained. “We have shown that [CC-92480] has profound anti-myeloma and immune-stimulatory activities in preclinical models, [which] have translated clinically into potent antiproliferative and tumoricidal effects in myeloma cell lines, including those resistant to lenalidomide and pomalidomide.”
In this phase I trial, investigators evaluated CC-92480 plus dexamethasone in patients whose myeloma had progressed on or within 60 days of their last therapy or whose myeloma was resistant or intolerant to other therapies and who were not considered candidates for currently available therapies.
Dexamethasone was administered at 40 mg weekly or 20 mg in patients ≥75 years of age. CC-92480 was administered at escalating doses according to several treatment schedules:
- 1-1.0 mg once daily (10 out of 14 days)
- 8-1.0 mg once daily (21 out of 28 days)
- 2-0.8 mg twice daily (3 out of 14 days)
- 6-2.0 mg once daily (7 out of 14 days)
At the time of the presentation, 66 patients had received CC-92480 plus dexamethasone. Participants’ median age was 66 years (range = 40-78), and the median number of prior therapies was 6 (range = 2-13). The most common prior therapies included a proteasome inhibitor (100%), lenalidomide (97%), pomalidomide (92%), and hematopoietic cell transplantation (76%). Half of the patients were considered to have triple-class refractory disease.
As of the data presentation, approximately one-third of patients remained on CC-92480 treatment, Dr. Richardson reported. Of the 51 patients who discontinued treatment, the main cause was progressive disease (n=39), followed by withdrawal (n=5), death (n=5), and adverse events (AEs; n=1). None of the deaths were considered related to CC-92480, he noted.
Across the dosing cohorts, 10 patients had dose-limiting toxicities, most commonly neutropenia. The researchers determined that the maximum tolerated dose of CC-92480 was 1.0 mg for both the 10/14-day schedule and 21/28-day schedules.
The most common AEs observed in the study population were neutropenia (74%), infections (71%), and anemia (55%). Dr. Richardson added that neutropenia was also the most common grade 3-4 AE, reported in 49 patients. Neutropenia was managed with dose modification and granulocyte colony-stimulating factor, while most infections were successfully managed with antibiotics and supportive care.
The researchers observed that systemic exposure to CC-92480 increased in a dose-constant fashion, correlating with pharmacodynamic effects, Dr. Richardson reported. They also observed that more consecutive days of treatment helped prevent rebound of serum myeloma paraproteins, supporting the 21/28-day treatment schedule.
Preliminary efficacy analyses revealed an overall response rate of 21% across all dosing cohorts, but this increased to 40% with the maximum tolerated dose (1.0 mg once daily for 10/14 days) and 55% with the recommended phase II dose (1.0 mg once daily for 21/28 days).
The implications of this study are limited by the small patient population and the lack of a comparator arm, but Dr. Richardson called the findings “encouraging,” noting that the study is ongoing to further optimize the dose and schedule.
Study authors report relationships with Celgene/BMS, the manufacturer of CC-92480.
Richardson PG, Vangsted AJ, Ramasamy K, et al. First-in-human phase 1 study of the novel CELMoD agent CC-92480 combined with dexamethasone in patients with relapsed/refractory multiple myeloma. Abstract S208. Presented as part of EHA25 Virtual; July 12, 2020.