First-in-Human Trial of Novel Therapy Shows Promising Results in Relapsed/Refractory Multiple Myeloma

CC-92480, a novel cereblon E3 ligase modulator agent, in combination with dexamethasone appeared safe and active in patients with heavily pretreated relapsed or refractory multiple myeloma, according to data presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.
 
BY Ryan McDonald
PUBLISHED May 31, 2020
Results from an ongoing multicenter trial presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program demonstrated that CC-92480, a novel cereblon E3 ubiquitin ligase modulating agent, in combination with dexamethasone appeared safe and active in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM).

“CC-92480, as a novel CELMoD (cereblon E3 ligase modulator) agent, has promising activity preclinically, and this has been successfully translated to the clinic with a manageable safety profile in patients with heavily pretreated RRMM,” meaning disease that has been resistant to previous treatment or has recurred, Dr. Paul G. Richardson, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in his presentation.

A CELMoD is a targeted drug that inhibits the activity of the protein cereblon, setting off a chain reaction that modifies immune response and also directly fights cancer.

To evaluate the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of CC-92480 plus the steroid dexamethasone, 76 patients (median age, 66 years; range, 44-78) with heavily pretreated RRMM were enrolled in the phase 1 dose-escalation study.

Patients within the study had received a median of six prior treatment regimens. All patients had received a previous proteasome inhibitor, 97.4% received Revlimid (lenalidomide), 92.1% received Pomalyst (pomalidomide), 75% received anti-CD38 antibodies and 76.3% had received autologous stem cell transplantation.

For patients to be eligible to be in the study, they had to have experienced disease progression on or within 60 days of their last therapy, as well as resistance or intolerance to other multiple myeloma therapies, or ineligibility for them.

The overall response rate (ORR, meaning the proportion of patients who had a partial or complete response to treatment) was 21.1% among the overall patient population — with one complete response, six very good partial responses, nine partial responses and four minimal responses.
The efficacy of the combination was dependent on the dose level and treatment schedule.

Patients received CC-92480 on either a continuous or intensive dosing schedule. Treatment began at 0.1 milligrams (mg) and was escalated up to 1 mg – the maximum tolerated dose – per day for 10 out of 14 days during a 28-day cycle in the continuous schedule cohorts.

However, after noting that patients needed longer continuous breaks to recover their neutrophil counts, researchers switched to a 21 out of 28-day schedule.

Patients on the intensive schedule received 0.2 mg of study drug, which was escalated up to 0.8 mg twice a day, administered three out of 14 days twice a month. However, that schedule was eventually changed to 1.6 mg to 2 mg once daily for seven out of 14 days twice a month.

The ORR was 40% in patients treated with the 10 out of 14-day continuous dosing schedule and 54.5% in those treated in a 21 out of 28-day continuous schedule.

The most common treatment-emergent side effects of any grade across the study population included a deficiency of neutrophils in the blood (73.7%), infections (71%), anemia (55.3%), a deficiency of platelets in the blood (43.4%) and fatigue (38.2%). Dose-limiting side effects among the different patient groups were mostly associated with neutrophil deficiency.

Dose reduction of CC-92480 occurred in 22.4% of patients, and there were no discontinuations due to treatment-related side effects.

At the time of the data cutoff, 25 patients were still receiving therapy. Progressive disease caused 51.3% of patients to discontinue treatment. Five patients died during the study; however, no deaths were considered related to the study drug.

“Especially important for our patients (is that) we have seen really promising activity at therapeutic doses in patients who are truly refractory not only to pomalidomide, but also to proteasome inhibition and monoclonal antibody therapy in the setting of extramedullary disease,” Richardson said. “Going forward, there is now a phase 1/2 study evaluating the safety and efficacy of (CC-92480) in combination with other standard treatments in patients with relapsed/refractory multiple myeloma, and these results will hopefully validate what we have seen to date.”

A version of this story originally appeared on OncLive® as “CC-92480 Shows Encouraging Efficacy in First-in-Human Study for R/R Multiple Myeloma.
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