AML-187: The STIMULUS Clinical Trial Program: Evaluating Combination Therapy with MBG453 in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) or Acute Myeloid Leukemia

Context TIM-3, an inhibitory receptor with a key role in regulating adaptive and innate immunity, is expressed on multiple immune cell types as well as leukemic stem cells and blasts, but not normal hematopoietic stem cells, making it a promising target in MDS and AML. In a phase 1b study ( NCT03066648 ), the anti–TIM-3 monoclonal antibody, MBG453, plus decitabine showed promising preliminary efficacy with a good safety profile in patients with higher-risk MDS or AML (Borate et al, ASH 2019). Objective The STIMULUS clinical trial program is evaluating the efficacy and safety of MBG453 combination therapy in patients with HR-MDS or AML. Design Two study designs from the STIMULUS clinical trial program are described. STIMULUS-MDS1 (N≈120; NCT03946670 ) is a double-blind study evaluating whether MBG453 plus hypomethylating agents (HMA) improves complete remission (CR) rate and progression-free survival (PFS) vs HMA alone in HR-MDS. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival (LFS), transfusion independence, safety, pharmacokinetics, and immunogenicity. Eligible patients are treatment-naive, aged ≥18 years, with HR-MDS (IPSS-R high-/very high-risk MDS, or intermediate-risk MDS with ≥5% bone marrow blasts). Patients are randomized 1:1 to receive MBG453 400 mg or placebo IV D8, D22, plus decitabine 20 mg/m2 IV D1–D5; or azacitidine (AZA) 75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9 of each 28-day cycle. This study is currently recruiting patients worldwide. STIMULUS-AML1 (N≈86; NCT04150029 ) is an open-label study evaluating the safety (incidence of dose-limiting toxicities) and efficacy (CR rate) of MBG453+AZA+venetoclax. Secondary endpoints include safety and tolerability, CR/CRi rate, MRD-negative rate, CR durability, relapse-free survival, EFS, OS, pharmacokinetics, transfusion independence, and immunogenicity. Eligible patients are adults with newly diagnosed untreated AML who are not suitable for IC or HSCT based on age (≥75 years old) or comorbidities (including renal impairment, cardiac and pulmonary comorbidities). Part 1 is a safety run-in (n≈18) across 2 MBG453 dose levels (400/800 mg IV D8 of each 28-day cycle) plus AZA (75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9) and venetoclax 400 mg PO QD. If the triplet is assessed to be safe, Part 2 (expansion; n≈68) will investigate MBG453 at 800 mg Q4W in combination with AZA+venetoclax.