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Background: Therapy options for pts with HR-MDS or AML who are not candidates for intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) are limited, and clinical outcomes are poor. Novel, effective and tolerable therapies are urgently needed. TIM-3 is an inhibitory receptor that regulates both adaptive and innate immune responses. It is expressed on immune cells and on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS and AML. Sabatolimab is a high-affinity, humanized, anti-TIM-3 IgG4 (S228P) antibody that simultaneously targets TIM-3 on immune and myeloid cells; this may restore immune function while also directly targeting LSCs and blasts. In preclinical studies, sabatolimab enhanced immune cell-mediated killing of AML cells in vitro. In early results from a ph 1b study (NCT03066648), sabatolimab + hypomethylating agents (HMAs; decitabine [Dec] or azacitidine [Aza]) demonstrated encouraging overall response rates in pts with high-/very high-risk MDS (+ Dec, 61%; + Aza, 57%) and newly diagnosed AML (+ Dec, 47%; + Aza, 29%), and a favorable safety profile. Study Design and Methods: The STIMULUS clinical trial program currently includes 3 trials evaluating the efficacy and safety of sabatolimab combination therapy in pts with HR-MDS or AML who are ineligible for IC or HSCT: STIMULUS-MDS1 (NCT03946670; ph 2) in pts with HR-MDS, STIMULUS-MDS2 (NCT04266301; ph 3) in pts with HR-MDS or chronic myelomonocytic leukemia-2 (CMML-2), and STIMULUS-AML1 (NCT04150029; ph 2) in pts with AML. STIMULUS-MDS1 is a randomized, double-blind, placebo-controlled ph 2 study evaluating the addition of sabatolimab to HMA in pts with HR-MDS. The 2 primary endpoints are complete remission (CR) rate and/or progression-free survival. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival, duration of CR, transfusion independence, safety, pharmacokinetics (PK), and immunogenicity. Approximately 120 pts will be randomized 1:1 to receive sabatolimab 400 mg or placebo IV Q2W (D8 and D22 of each 28-d cycle), + Dec 20 mg/m2 IV on D1-D5 or Aza 75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9, of each 28-d cycle. STIMULUS-MDS2 is a randomized, double-blind, placebo-controlled ph 3 study of sabatolimab in combination with Aza in pts with HR-MDS or CMML-2; the primary endpoint is OS. Secondary endpoints include measures related to pt quality of life, such as time to definitive deterioration of fatigue, improvement of fatigue, transfusion-free intervals, and physical/emotional functioning, as well as additional efficacy and safety parameters. Approximately 500 pts will be randomized 1:1 to sabatolimab 800 mg or placebo IV Q4W at D8 of each 28-d cycle + Aza using the same Aza dosing schedule as in STIMULUS-MDS1. Eligible pts for STIMULUS-MDS1 or -MDS2 are treatment-naïve adults with HR-MDS (Revised International Prognostic Scoring System [IPSS-R] intermediate-/high-/very high-risk MDS). Pts with intermediate-risk MDS enrolling in STIMULUS-MDS1 are also required to have ≥5% bone marrow blasts at baseline. Pts with CMML-2 are eligible for STIMULUS-MDS2 only. STIMULUS-AML1 is a single-arm ph 2 study evaluating the safety and efficacy of sabatolimab in combination with Aza and venetoclax in pts with AML who are not candidates for IC or HSCT. Primary endpoints are incidence of dose-limiting toxicities (safety run-in) and CR rate. Secondary endpoints include safety and tolerability, CR/CRi rate, measurable residual disease-negative rate, durability of CR, relapse-free survival, EFS, OS, PK, transfusion independence, and immunogenicity. Eligible pts for STIMULUS-AML1 are adults with newly diagnosed AML who are not candidates for IC or HSCT, based on comorbidities (including renal and hepatic impairments, cardiac and pulmonary comorbidities), age (≥75 years old), or Eastern Cooperative Oncology Group performance status of 2 or 3. STIMULUS-AML1 will enroll approximately 86 pts. Part 1 consists of a safety run-in (≈18 pts) across 2 escalating sabatolimab dose levels (400/800 mg IV Q4W on D8 of each 28-d cycle) in combination with Aza (75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9) and venetoclax 400 mg PO QD. If this triple combination is assessed to be safe, part 2 (expansion) will open and enroll approximately 68 additional pts who will receive sabatolimab 800 mg Q4W in combination with Aza and venetoclax. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kim:SL VaxiGen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; BL&H: Research Funding; Sanofi Genzyme: Honoraria; Abbvie: Honoraria. Miyazaki:Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Platzbecker:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malek:Novartis: Current Employment. Scott:Novartis: Current Employment. Niolat:Novartis: Current Employment. Peyrard:Novartis: Current Employment. Ma:Novartis: Current Employment. Kiertsman:Novartis: Current Employment. Stegert:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Hertle:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria.

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. Disclosures Zeidan: Cardinal Health: Consultancy, Honoraria; MedImmune/AstraZeneca: Research Funding; Jazz Pharma: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria; Chugai: Research Funding; Otsuka: Honoraria. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Malek:Novartis: Employment; Novartis: Equity Ownership. Niolat:Novartis Pharma: Employment. Kiertsman:Novartis Pharmaceuticals Corporation: Employment, Other: Employment includes stock options. Fenaux:Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: MBG453 is an investigational anti-TIM-3 antibody that is being evaluated in hematological malignancies and solid tumors