First-in-Human Study Shows Favorable Activity With CC-92480 in Relapsed/Refractory Myeloma

Paul G. Richardson, MD

Favorable activity and safety findings were demonstrated with the combination of CC-92480 plus dexamethasone as treatment of patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in an ongoing study, according to a presentation from the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

In the phase 1 multicenter, dose-escalation trial (NCT03374085), there was an overall response rate (ORR) of 21.1%—with 1 complete response (CR), 6 very good partial responses (VGPRs), 9 PRs, and 4 minimal responses (MRs)—observed among the overall patient population. The efficacy of the combination was dependent on the dose level and schedule the patients were on.

“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,” Paul G. Richardson, MD, the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in his presentation.

CC-92480 was administered in either a continuous or an intensive dosing schedule. In the continuous schedule cohorts, treatment started at 0.1 mg daily and escalated up to the maximum tolerated dose (MTD) of 1.0 mg per day administered for 10 out of 14 days (10/14) in a 28-day cycle after 2 dose-limiting toxicities (DLTs) were observed. The patients receiving the 10/14-day schedule had deep Aiolos degradation but needed a longer continuous break to recover their neutrophil counts. Based on this, the investigators switched to a 21/28-day schedule and decided this was the best schedule for the MTD of 1.0 mg.

For the intensive schedule, patients received 0.2 mg escalated up to 0.8 mg twice a day, administered 3 out of 14 days twice a month, which was then adapted to 1.6 mg to 2.0 mg once daily for 7/14 days twice a month. The 3-day schedule was associated with deep Aiolos degradation, but patients needed more time on treatment to prevent the rebound of serum myeloma paraproteins.

Although the investigators were able to dose escalate up to 2.0 mg daily, the 1.0 mg dose for the 21/28-day continuous schedule was determined to be the recommended phase 2 dose after several DLTs were observed.

Ages of the 76 total patients ranged from 44 to 78 years old, with the median being 66 years old. The ECOG performance status of these patients ranged from 0 to 2, with a majority of patients having a status of 1 (63.2%). They had stage I to III disease by the International Staging System at baseline, with 44.7% patients at stage II and 22.4% at stage III. In this trial, 36.8% of patients had extramedullary plasmacytoma. The time from initial diagnosis was 7.2 years (range, 0.9-23).

The median number of prior regimens for patients in this study was 6 (range, 2-13). These therapies included proteasome inhibitor (PI) therapy in 100% of patients, lenalidomide in 97.4%, pomalidomide in 92.1%, anti-CD38 antibodies in 75.0%, and autologous stem cell transplantation in 76.3%. There were 73.7% of patients who were lenalidomide-refractory, 78.9% who were pomalidomide-refractory, and another 73.7% who were PI-refractory.

“Those who were truly refractory to monoclonal antibody therapy was 70%, and thus in aggregate in terms of triple-class refractory disease. In fact, 50% of the patients constituted this exquisitely vulnerable population,” Richardson said.

The primary end points of this trial were to find the MTD, the recommended phase 2 dose, safety, tolerability and pharmacokinetics of this combination for patients with RRMM. Patients eligible to be on the study were those who had progression on or within 60 days of their last MM therapy, resistance or intolerance to, or not candidates for the therapies currently available in this setting. The main secondary end point was to assess preliminary efficacy.

The ORR was 40% in patients treated with a 10/14-day continuous dosing schedule and 54.5% with a 21/28-day continuous schedule. There was 1 CR, 1 VGPR, 2 PRs, and 1 MR in the 21/28-day group; 7 of the 11 patients on this schedule were triple class-refractory.

Among patients treated with the continuous dosing schedules, DLTs were reported in 3 out of 11 patients treated at 1.0 mg in the 21/28-day cohort and 2 out of 10 patients treated at 1.0 mg in the 10/14-day cohort. Grade 4 DLTs in the 21/28 group were neutropenia and sepsis; grade 4 DLTs in the 10/14 group were neutropenia and febrile neutropenia. In the intensive schedule cohorts, 2 patients treated with 2.0 mg once daily of CC-92480 for 7/14 days experienced a total of 4 DLTs, including grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase, and grade 2 pneumonitis.

The most frequent treatment-emergent adverse events (TEAEs) of any grade included neutropenia in 73.7% of all 76 patients, infections in 71%, anemia in 55.3%, thrombocytopenia in 43.4%, and fatigue in 38.2%. DLTs in the different cohorts were mostly due to neutropenia. The most frequent grade 3 toxicities were infections at 32.9% and neutropenia at 30.3%, and grade 4 toxicities were neutropenia at 34.2% and thrombocytopenia at 9.2%.

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

“For a relapsed/refractory population, this is fairly typical,” Richardson said. “In terms of AEs of interest, there was little in the way of peripheral sensory neuropathy, just 5%; and importantly, there was only one case of deep vein thrombosis.”

At the time of the data cutoff, there were 25 patients, or 32.9%, still on therapy. Progressive disease caused 51.3% of patients to discontinue treatment. There were 5 deaths during this study, but none were due to CC-92480.

CC-92480, a potent CELMoD agent, was designed for rapid and maximal degradation of target proteins, such as Aiolos and Ikaros. The basis for this study was the drug’s “impressive” immune-stimulatory and antimyeloma activity in preclinical models, as well as its potent antiproliferative and tumoricidal activity in MM cell lines, including in patients who are resistant to lenalidomide and pomalidomide. It also had synergy with the standard-of-care therapies for these patients, such as dexamethasone, PIs, and monoclonal antibodies.

_Reference

_{Richardson PG, Vangsted AJ, Ramasamy K, et al. 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). J Clin Oncol. 2020;38(suppl 15):8500. doi:10.1200/JCO.2020.38.15_suppl.8500}