An Open-Label, Multicenter, Phase Ib Study of the Anti-TIM3 Monoclonal Antibody BC3402 in Combination with Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Background: BC3402 is a monoclonal antibody (mAb) targeting the T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, which was originally identified as a receptor expressed on interferon-γ-producing CD4+ and CD8+ T cells. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or ‘exhausted’ T cells in chronic viral infections and cancer. To date, BC3402 has demonstrated a favorable safety profile, pharmacokinetic (PK) characteristics and activity as a single agent in treating patients (pts) with solid malignances. This is the first report on an ongoing phase Ib study of BC3402 in combination with azacitidine (AZA) in pts with higher-risk MDS or CMML.

Method: This Phase Ib, open-label, multicenter, dose escalation and expansion study evaluated the safety, PK, pharmacodynamics, and preliminary activity of BC3402 combined with AZA in pts with higher-risk MDS (intermediate-, high-, or very high-risk by IPSS-R) or CMML. Three dose-schedules of BC3402 are being evaluated (10 mg/kg every 4 weeks (Q4W), 10 mg/kg every 2 weeks (Q2W) and 20 mg/kg Q2W) combined with AZA at a fixed dose of 75 mg/m²/day on Days 1-7 every 28 days. An accelerated titration design was used in the first dose level followed by a standard “3+3” design. A recommended phase 2 dose (RP2D) is being selected for dose expansion. Disease assessments are performed by IWG 2006 criteria for MDS and CMML.

Results: As of the data cut-off date (June 7^th, 2024), 10 pts (7 MDS, 3 CMML) were enrolled including 8 pts in the dose escalation part (10 mg/kg Q4W [1], 10 mg/kg Q2W [3], and 20 mg/kg Q2W [4]) and 2 pts in the dose expansion part. DLT has not been observed and 20 mg/kg Q2W has been determined to be the RP2D. All pts experienced treatment-related adverse event (TRAE), with 9 pts (9/10, 90%) experiencing Grade ≥ 3 TRAEs. The most common (incidence≥25%) TRAEs are neutrophil count decreased (90%), white blood cell decreased (90%), platelet count decreased (90%), anemia (50%), and lymphocyte count decreased (30%). All of the TRAEs were manageable. Of the 3 treatment naïve MDS pts treated with BC3402 10 mg/kg Q2W, two pts had complete remissions (CRs). Of the 6 pts treated with BC3402 20 mg/kg Q2W, one treatment naïve MDS and two treatment naïve CMML pts had CRs giving an overall CR rate of 71.4% (5/7) among the total of 7 treatment naïve pts. The duration of treatment for these CR pts are range from 6.3 to 11.4 months, all of whom are still receiving study treatment.

Conclusion: BC3402 at dose range up to 20 mg/kg Q2W combined with AZA demonstrated promising anti-tumor efficacy (CR rate: 71.4%) in treatment naïve MDS and CMML patients and AEs were manageable. Given the CR rate of ~16% with AZA monotherapy in this patient population, the current data supports further evaluation of BC3402 in combination with AZA for pts with treatment naïve MDS and CMML. Clinical trial information: NCT05970822.