Early-Phase Trial Suggests Bispecific Antibody CC-93269 Has Activity in Relapsed/Refractory Multiple Myeloma

Watch our interview with Luciano J. Costa, MD, PhD.


CC-93269, a bispecific antibody that binds B-cell maturation antigen (BCMA) on malignant plasma cells and CD3 on T cells, was reported to have a “manageable” safety profile in patients with heavily pretreated multiple myeloma (MM), although several patients developed cytokine release syndrome (CRS), which was fatal in 1 patient, according to results of a phase I trial presented at the 2019 ASH Annual Meeting. Lead investigator Luciano J. Costa, MD, PhD, from the University of Alabama at Birmingham, noted that CC-93269 was associated with a high rate of response, including achievement of measurable residual disease (MRD) negativity in some patients.

In animal and preclinical models, CC-93269 induced tumor regression and promoted myeloma cell death, Dr. Costa explained. Based on these results, researchers conducted this first-in-human phase I trial, which evaluated the safety and tolerability of the agent in patients with relapsed/refractory MM who had previously received 3 or more regimens and who were naïve to BCMA-directed therapy.

CC-93269 was administered in 28-day cycles. Participants received intravenous CC-93269 on days 1, 8, 15, and 22 of cycles 1 to 3, on days 1 and 15 of cycles 4 to 6, and on day 1 of cycle 7.

The dose-escalation trial was conducted in two stages:

  • stage 1: fixed doses of CC93269 were administered to patients
  • stage 2: fixed first dose of CC-93269 on day 1 of cycle 1, followed by intrapatient dose escalation on day 8 of cycle 1

As of October 28, 2019 (data cutoff), a total of 30 patients had received CC-93269. This was a heavily pretreated population, Dr. Costa noted, with a median of 5 prior regimens (range = 3-13). All patients had been exposed to a proteasome inhibitor and an immunomodulatory drug, and more than three-quarters of participants had disease that was refractory to these treatments. In addition, 97% of patients had received an anti-CD38 monoclonal antibody and 77% had undergone autologous hematopoietic cell transplantation.

Throughout the study, CC-93269 doses ranged from 0.15 mg to 10 mg, with 7 patients treated with doses ≤3 mg, 14 with doses ranging from 3-6 mg, and 9 with doses of 6−10 mg.

During follow-up, nearly all patients (n=29; 97%) experienced at least 1 treatment-emergent adverse event (AE), including 73% (n=22) who experienced a grade ≥3 AE. The most common grade ≥3 AEs included:

  • neutropenia (43%; n=13)
  • anemia (37%; n=11)
  • infections (30%; n=9)
  • thrombocytopenia (17%; n=5)

Any-grade CRS developed in 23 patients (77%), including 1 with grade 5 CRS. CRS was most frequently associated with the first dose of CC-93269, and these events were successfully managed until resolution with dexamethasone and tocilizumab in most patients.

Four patient deaths occurred during study follow-up, 1 of which was attributed to CRS. The patient had received CC-93269 at an initial dose of 6 mg and a second dose of 10 mg, Dr. Costa reported. The other 3 causes of death (sepsis, sudden cardiac death, and general health deterioration due to progressive myeloma) “were not suspected to be related to the study drug,” he added.

Preliminary efficacy results suggested that CC-93269 has clinical activity in patients with relapsed/refractory MM, but only in patients receiving higher doses of the drug. No patients receiving ≤3 mg responded, but the overall response rates (defined as partial response or better) in patients treated with CC-93269 3-6 mg and >6 mg were 36% and 89%, respectively.

Overall, the rate of stringent complete response (sCR) was 17%, but, among the 9 patients receiving CC-93269 10 mg, the sCR rate was 44%.

Among responders, the median time to response was 4.1 weeks (range = 4.0-13.1), and 11 responses were ongoing at time of data cutoff. Most responders (92%) also were able to achieve MRD negativity. “MRD negativity was achieved very early,” said Dr. Costa, “and in most cases this was demonstrated already at the end of the first cycle.” Responses were further demonstrated by a clear dose-dependent decline in M (myeloma) protein, he added, with rapid declines observed in the 10 mg cohorts.

Although the rate of CRS and other AEs was high, Dr. Costa concluded that “the [efficacy and] safety profile of CC-93269 supports further development.” He added that trial enrollment is ongoing to define the recommend phase II dose of CC-93269. Limitations of this early-phase study include the short follow-up, the small number of enrolled patients, and the lack of a control arm.

Several study authors report relationships with Celgene, which sponsored the trial.

Reference

Costa LJ, Wong SW, Bermúdez A, et al. First clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (pts) with relapsed/refractory multiple myeloma (RRMM): interim results of a phase 1 multicenter trial. Abstract #143. Presented at the 2019 ASH Annual Meeting, December 7, 2019; Orlando, FL.