Interim results from the first study of CC-93269 in patients with relapsed/refractory multiple myeloma

CC-93269 is a humanized 2+1 IgG T cell engager that binds bivalently to B-cell maturation antigen (BCMA) on myeloma cells and monovalently to CD3ε on T cells, leading to T cell activation and myeloma cell death.¹

At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Luciano J. Costa, Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, US reported the interim results from the phase I dose-finding study, CC-93269-MM-001 (NCT03486067), that evaluated CC-93269 in patients with relapsed/refractory multiple myeloma (RRMM).²

Study design²

• Eligible patients (N= 30) had received ≥ 3 prior lines of therapy, had progressed within 60 days of their last regimen, and had not received prior anti-BCMA therapy
• Median patient age was 64 years (range 42–78) and median time since initial diagnosis was six years (range; 1.4–16.6); eight (26.7%) patients had extramedullary lesions and nine (30%) had high-risk cytogenetics
• The median number of prior regimens was five (range; 3–13):
  • Of 30 (100%) patients exposed to proteasome inhibitors (PIs), 23 (76.7%) were refractory to the last PI treatment
  • Of 30 (100%) patients exposed to immunomodulatory drugs (IMiDs), 24 (80%) were refractory to the last IMiD treatment
  • Of 29 (96.7%) patients exposed to anti-CD38 monoclonal antibodies, 24 (80%) were refractory to the last anti-CD38 monoclonal antibody treatment
• The study design included a dose-escalation part that will be followed by a cohort expansion The dose-escalation involved two stages:
  • Stage one: fixed doses of CC‑93269
  • Stage two: fixed first dose on Cycle one Day one, followed by a step-up in dose on Cycle one Day eight
• In the dose-escalation phase, CC-93269 was administered intravenously over two hours. Patients received CC-93269 on Days one, eight, 15, and 22 of Cycles 1–3; on Days one and 15 of Cycles 4–6; and on Day one of Cycle seven onwards, for up to two years
• The doses of CC-93269 ranged from 0.15 mg to 10 mg
  • In stage one, fixed doses were administered to single patient cohorts (Cohorts 1–3) followed by cohorts of three to four patients (Cohorts 4–6), with doses increasing to 10 mg in Cohort six with no dose-limiting toxicity (DLT) observed
  • Stage two was initiated with a step-up from 6 mg on Day one to 10 mg on Day eight in Cohort seven
    • Due to one patient experiencing severe cytokine release syndrome (CRS), cohorts eight and nine (with a patient population of low tumor burden and high tumor burden, respectively) received 3 mg on Day one and 6 mg on Day eight
  • Primary endpoints were safety and tolerability of CC-93269 including adverse events (AEs), maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase II dose (RP2D)

Results²

Safety

• Almost all patients (96.7%) had treatment-emergent AEs (TEAEs), with one or more grade ≥ 3 TEAEs reported in 22 (73.3%) patients
• The majority of grade ≥ 3 TEAEs were hematologic and included 13 (43.3%) patients with neutropenia, 11 (36.7%) with anemia, and five (16.7%) with thrombocytopenia
• The most common non-hematologic TEAEs of any grade were CRS (n= 23 [76.7%]), and infections and infestations (n= 17 [56.7%])
• Four deaths occurred within 35 days of the last dose of CC-93269:
  • One of these was suspected to be related to CC-93269 and manifested as CRS. This patient received 6 mg of CC-93269 as a first dose and 10 mg on Cycle one Day eight
• In 76.7% of cases, CRS occurred after the first dose of CC-93269 and became less common with subsequent doses:
  • The majority (73.3%) of CRS events were grade one (n= 15) or two (n= 7) with just one event of grade ≥ 3
  • CRS started at a median time of one day (range; 1─9) from the first dose and resolved at a median time of two days (range; 1─6)
  • Tocilizumab was administered to 13 (43.3%) patients and corticosteroids to 22 (73.3%) patients
  • Patients treated with a dose of CC-93269 ≥ 6mg received prophylactic dexamethasone

Efficacy

• The overall response rate (ORR) in all patients was 43.3% with a stringent complete response/complete response (sCR/CR) of 16.7%
• The likelihood of response was dose-dependent. ORR by CC-93269 dose:
  • Dose ≤ 3mg (n= 7): 0%
  • Dose 3 to 6 mg or fixed-dose 6 mg (n= 14): 7%
  • Dose 6 to 10 mg or fixed-dose 10 mg (n= 9): 88.9%
• Among the nine patients treated with 10 mg of CC-93269, the ORR was 88.9% with a sCR/CR of 44.4%
• The median time to response was 4.1 weeks (range; 4–13.1)
• Among 13 responding patients, 11 responses are ongoing
• Measurable residual disease (MRD) negativity was achieved by 12 of the 13 responding patients
• The NTD, MTD, and RP2D have not yet been reached

Conclusions²

• CC-93269 shows a manageable safety profile and promising dose-dependent efficacy in patients with RRMM who have received ≥ 3 prior lines of therapy
• Based on the promising results of the interim analysis, enrollment continues in order to define the RP2D