The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

According to results presented at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, more than 40% of heavily pretreated patients with refractory multiple myeloma enrolled in an ongoing phase 1 study of a novel bispecific antibody achieved a response.1

Previous preclinical studies have demonstrated that crosslinking of myeloma plasma and CD3-positive T cells using a bispecific antibody that binds bivalently to tumor necrosis factor receptor B-cell maturation antigen (BCMA) on myeloma plasma cells and monovalently to CD3-positive T cells results in T-cell activation. Subsequent release of cytokines and enzymes cause myeloma cell death.2

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Reported here is an interim analysis of an open-label, dose-finding, first-in-human, phase 1 study (ClinicalTrials.gov Identifier: NCT03486067), which evaluated this immunoglobulin G-based bispecific antibody (ie, CC-93269) in 30 adult patients with heavily pretreated relapsed/refractory multiple myeloma.

Part A of the study involved dose escalation to determine the maximum tolerated dose (MTD) and nontolerated dose (NTD) of CC-93269 administered intravenously. The dose-expansion portion of the study (part B) was designed to assess the efficacy and safety of the study drug administered at or below the MTD in selected cohorts so as to determine the recommended phase 2 dose (RP2D).

During part A of the study, CC-93269 was administered in fixed monthly cycles on days 1, 8, 15, and 22 of cycles 1 to 3, days 1 and 15 of cycles 4 through 6, and only on day 1 for cycle 7 and beyond for up to 2 years.

Stage I of part A of the study involved administration of fixed doses between 0.15 to 10 mg to 6 patient cohorts, whereas “stepped-up” doses of either 3 mg (day 1) to 6 mg (day 8) or 6 (day 1) to 10 mg (day 8) were administered to patients in cohorts 7, 8 (patients low tumor burden), and 9 (patients with high tumor burden) during stage II of the study.

At baseline, the median age of the study patients was 64 years, with a median of 5.94 years since initial diagnosis of multiple myeloma, and a median of 5 prior regimens for the treatment of multiple myeloma. Extramedullary disease and high-risk cytogenetics were present in 26.7% and 30.0% of patients, respectively.

Previous treatment included a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody for 100%, 100%, and 96.7% of patients, respectively. Furthermore, patients had disease refractory to last administration of these respective agents in 76.7%, 80%, and 80% of cases, with two-thirds of patients refractory to all 3 classes of drugs.

At the time of data analysis, 73.3% of patients had experienced 1 or more grade 3/4 treatment-emergent adverse effects, with grade 3 or higher neutropenia, anemia, infections, and thrombocytopenia occurring in 43.3%, 36.7%, and 16.7% of patients, respectively.

Cytokine release syndrome (CRS) occurred in 76.7% of patients, and the frequency of CRS appeared to increase in concert with the dose of the study drug. Most CRS events were grade 1/2, and occurred during cycle 1 after the first dose of study drug in approximately three-quarters of patients experiencing this adverse effect of treatment.

CRS was managed with corticosteroids or tocilizumab, and dexamethasone prophylaxis was administered to all patients receiving CC-932269 at an initial dose of 6 mg or higher.

There were 4 patient deaths that occurred within 35 days of the last dose of study drug, although only 1 of these deaths was considered to be treatment–related and occurred in the setting of CRS; this patient had a high tumor burden, and received an initial dose of study drug of 6 mg followed by 10 mg during cycle 1.

For all study patients, the overall response rate (ORR) was 43.3%, with a stringent complete response (sCR)/CR rate of 16.7%, and bone marrow minimal disease negativity in 92.3% of responding patients. Of the 9 patients treated with an initial dose of study drug of at least 6 mg, the ORR was 88.9%, with 44.4% and 33.3% of them achieving a sCR/CR or very good partial response, respectively.

The median time to response was 4.1 weeks, and 11 of 13 responses were ongoing at a follow-up.

In his concluding remarks, Luciano J. Costa, MD, PhD, from the University of Alabama at Birmingham — who presented the study findings — stated that “CC-93269 shows promising dose-dependent efficacy, including MRD-negative sCRs, with a convenient administration schedule, in patients with heavily pretreated relapsed/refractory multiple myeloma.”

Disclosures: Three or more study authors disclosed relationships with Janssen, Takeda, and Sanofi. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.

References

  1. Costa LJ, Wong SW, Bermudez 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. Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019: Orlando, Florida. Abstract 143.
  2. Seckinger A,  Delgado JA, Moser S, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31:396-410.