A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of MBG453 Added to Hypomethylating Agents (HMAs) in Patients (pts) with Intermediate, High, or Very High Risk Myelodysplastic Syndrome (MDS): Stimulus-MDS1

Background and Rationale: Pts with higher-risk (HR; intermediate, high, or very high risk) MDS experience poor outcomes and have limited treatment options as most such pts are older and not candidates for the only potentially curative therapy: allogeneic hematopoietic stem cell transplantation (alloHSCT). HMAs are approved for the frontline (1L) management of HR-MDS, but 50% of HMA-treated pts experience primary failure and most responders progress within 1-2 yr. Furthermore, pts often require 4-6 months of HMA therapy before a response is seen, and deep responses (e.g., complete responses or complete cytogenetic responses) are rare. Although azacitidine is the only drug shown to prolong overall survival (OS) in HR-MDS (AZA-001 study; Fenaux et al, 2009), accumulating evidence suggests that the median OS achieved with azacitidine at the population level may be shorter than the 24 months reported in this landmark trial. Thus, there is an urgent need for novel therapies in the 1L setting of HR-MDS.

T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an inhibitory receptor with a key role in regulating not only adaptive but also innate immune responses. TIM-3 is also preferentially expressed on leukemic stem cells and blasts, and expression of TIM-3 correlates with severity of MDS. TIM-3 is therefore a promising therapeutic target whose blockade may restore immune function-or reawaken immunity-while also directly targeting leukemic stem cells. MBG453 is a high-affinity, humanized, anti-TIM-3 IgG4 monoclonal antibody that blocks binding of TIM-3 to its ligand, phosphatidylserine. In an early clinical trial, MBG453 demonstrated a good safety/tolerability profile in pts with advanced solid tumors and an ongoing phase I study is evaluating MBG453 plus decitabine in HR-MDS and acute myeloid leukemia (AML). We present here the study design of an ongoing large, international, multicenter phase II clinical trial (STIMULUS-MDS1; NCT03946670) evaluating MBG453 combined with HMAs in 1L management of pts with HR-MDS.

Methods: The primary objective of this randomized, double-blind, placebo-controlled study is to evaluate whether addition of MBG453 to standard HMA improves the complete remission (CR) rate and progression-free survival (PFS) compared with HMA alone in pts with HR-MDS. Secondary objectives include assessment of OS, leukemia-free survival (LFS), transfusion independence, and safety, and characterization of pharmacokinetics and immunogenicity.

Eligible pts are aged ≥ 18 yr with a confirmed diagnosis of MDS categorized based on the Revised International Prognostic Scoring System (IPSS-R) as very high risk (> 6 points), high risk (> 4.5-6 points), or intermediate risk (> 3-4.5 points) with ≥ 5% bone marrow blasts at baseline. Pts considered candidates for alloHSCT at the time of screening are not eligible. Additional exclusion criteria include diagnosis of AML or chronic myelomonocytic leukemia, prior treatment with anti-TIM-3 therapy, or prior treatment for HR-MDS with chemotherapy or HMAs. Pts with therapy-related MDS are allowed.

Responses will be recorded using modified International Working Group 2006 criteria. PFS will be measured from randomization until progression, relapse from CR, or death. LFS will be measured from randomization until detection of ≥ 20% blasts in bone marrow/peripheral blood, or death. Biomarker assessments will be conducted using pt samples.

Approximately 120 pts will be randomized in a 1:1 ratio to receive either MBG453 combined with an HMA or placebo combined with an HMA in 28-d treatment cycles. Selection of the HMA (decitabine or azacitidine) is per investigator's choice based on local standard of care. Randomization will be stratified by the HMA and IPSS-R risk category. MBG453 (400 mg) or placebo will be administered intravenously (IV) on D8 and D22 of each cycle. Decitabine will be administered IV at 20 mg/m² on D1 to D5 of each cycle; azacitidine will be administered IV or subcutaneously at 75 mg/m² on D1 to D7 or, alternately, on D1 to D5 plus D8 and D9 of each cycle. All pts who discontinue study treatment will be followed for efficacy (if they have not progressed/relapsed) and survival status until approximately 108 PFS events have been observed or for up to 4 yr after the last pt is randomized.

This study is ongoing and will enroll pts in several countries, including the United States.