A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS). (STIMULUS-MDS1)

A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria

This Phase II was a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: MBG453; Drug: Hypomethylating agents; Drug: Placebo

Detailed Description

The 2 primary objectives were as follows:

To determine if MBG453 combined with standard HMA therapy improved complete remission in subjects with intermediate, high, or very high risk MDS.

To determine if MBG453 combined with standard HMA therapy improved progression free survival (PFS) in subjects with intermediate, high or very high risk MDS.

This Phase II study was a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk MDS not eligible for HSCT or intensive chemotherapy. A total of 127 subjects were randomized in a 1:1 ratio to treatment arms as follows:

• MBG453 400 mg IV Q2W and decitabine or azacitidine
• Placebo IV Q2W and decitabine or azacitidine

The randomization was stratified by 2 stratification factors: a) HMA (decitabine or azacitidine) selected by the investigator as per the local SOC and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. Crossover between treatment arms was not permitted at any time during the study.

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1140
    • Novartis Investigative Site
• Belgium
  • Brasschaat, Belgium, 2930
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Québec, Quebec, Canada, G1J 1Z4
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 625 00
    • Novartis Investigative Site
  • Prague, Czechia, 128 08
    • Novartis Investigative Site
• France
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Novartis Investigative Site
• Greece
  • Alexandroupoli, Greece, 681 00
    • Novartis Investigative Site
  • Larissa, Greece, 411 10
    • Novartis Investigative Site
  • Pátrai, Greece, 265 04
    • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Hungary
  • Nyíregyháza, Hungary, 4400
    • Novartis Investigative Site
  • Hajdu Bihar Megye
    • Debrecen, Hajdu Bihar Megye, Hungary, 4032
      • Novartis Investigative Site
• Italy
  • FI
    • Florence, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20162
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • RC
    • Reggio Calabria, RC, Italy, 89124
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Japan
  • Gifu, Japan, 500 8513
    • Novartis Investigative Site
  • Osaka, Japan, 545-8586
    • Novartis Investigative Site
  • Fukuoka
    • Fukuoka, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Fukushima
    • Fukushima, Fukushima, Japan, 960 1295
      • Novartis Investigative Site
  • Kanagawa
    • Isehara, Kanagawa, Japan, 259-1193
      • Novartis Investigative Site
  • Kumamoto
    • Kumamoto, Kumamoto, Japan, 860-0008
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 983 8520
      • Novartis Investigative Site
  • Nagasaki
    • Nagasaki, Nagasaki, Japan, 852-8501
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo Ku, Tokyo, Japan, 113-8677
      • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 06351
    • Novartis Investigative Site
  • Korea
    • Seoul, Korea, South Korea, 03080
      • Novartis Investigative Site
• Spain
  • Málaga, Spain, 29010
    • Novartis Investigative Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Novartis Investigative Site
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• Turkey (Türkiye)
  • Izmir, Turkey (Türkiye), 35100
    • Novartis Investigative Site
  • Atakum
    • Samsun, Atakum, Turkey (Türkiye), 55200
      • Novartis Investigative Site
  • Kocaeli
    • Köseköy, Kocaeli, Turkey (Türkiye), 41380
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center Medical Oncology & Therapeutic
    • Duarte, California, United States, 91010
      • City Of Hope National Med Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School Of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • The Cancer Institute of New Jersey
  • Ohio
    • Columbus, Ohio, United States, 73210
      • Ohio State Comprehensive Cancer Center James Cancer Hospital
  • Texas
    • Dallas, Texas, United States, 75251
      • Mary Crowley Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.

• Age ≥ 18 years at the date of signing the informed consent form (ICF)-. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R):

  • Very high
  • High
  • Intermediate with at least ≥ 5% bone marrow blast
• Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
• Not eligible at the time of screening, for hematopoietic stem-cell transplantation (HSCT) according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

• Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization.
• Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.
• History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
• Currently using or used within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
• Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment.
• Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
• Live vaccine administered within 30 Days prior to randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MBG453 + hypomethylating agents; Patients are taking MBG453 plus hypomethylating agents	Drug: MBG453; MBG453 is being administered i.v.; Other Names: Sabatolimab; Drug: Hypomethylating agents; Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.
Placebo Comparator: Placebo + hypomethylating agents; Patients are taking placebo plus hypomethylating agents	Drug: Hypomethylating agents; Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.; Drug: Placebo; Placebo is being administered i.v.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR) Rate	CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100*109/L AND Neutrophils ≥ 1.0*109/L AND Peripheral blasts 0%. Modified response criteria According to International Working Group (IWG) and as per World Health Organization (WHO) criteria for Myelodysplastic syndromes (MDS) as per investigator assessment.	average of 7 months
Progression Free Survival (PFS)	PFS is defined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment.	approx. 32 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) - Final PFS	PFS isdefined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause. This is an update of the Primary Outcome Measure PFS with data collected after assessment of the primary results.	approx. 48 months
Overall Survival (OS)	Time from randomization to death due to any cause	approx. 48 months
Event-free Survival (EFS)	EFS is defined as the time from randomization to lack of reaching complete response (CR) within the first 6 months, relapse from CR or death due to any cause, whichever occurs first. CR and relapse from CR were defined according to International Working Group (IWG) for Myelodysplastic Syndromes (MDS) as per Investigator assessment. For participants not reaching CR within the first 6 months, an EFS event at day 1 was considered.	approx. 48 months
Leukemia-free Survival (LFS)	LFS is defined as the time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per World Health Organization (WHO) 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause.	approx. 48 months
Response Rate of Complete Remission (CR)/Marrow Complete Remission (mCR)/Partial Remission (PR)/Hematopoietic Improvement (HI))	Percentage of complete remission (CR)/marrow Complete Remission (mCR)/partial remission (PR) & Hematological improvement (HI) as per investigator assessment according to IWG-MDS. CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100*109/L AND Neutrophils ≥ 1.0*109/L AND Peripheral blasts 0%. mCR: where the Bone marrow ≤5% blasts and blast count decrease by ≥50% compared to baseline with or without improved blood counts or with or without transfusions. PR: All CR criteria except bone marrow: ≥50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow >5%. HI: restoration or enhancement of the function of the body's blood cell-producing system that must last as least 8 weeks. HI definition is based on modified Hematological Improvement per IWG-MDS criteria in MDS & is the combination of Erythroid response (HI-E), Platelet response (HI-P) & Neutrophil response (HI-N).	approx. 32 months
Duration of Complete Remission	Duration of complete response is the time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first.	approx. 48 months
Time to Complete Remission	Time from randomization to the first documented CR	Average of 7 months
Percent of Participants Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS	Improvement in RBC/platelets transfusion independence. RBC/platelets transfusion independence rate is defined as the percentage of participants having received no RBC/platelets transfusions during at least 8 consecutive weeks after randomization.	approx. 48 months
Red Blood Cells (RBC) Transfusion Independence Duration After Randomization	The total duration of all transfusion independence periods is the sum of each period of the transfusion independence. RBC transfusions independence period is defined as the period for which participants having received no RBC transfusions during at least 8 consecutive weeks after randomization.	approx. 48 months
Platelets Transfusion Independence Duration After Randomization	The total duration of all transfusion independence periods is the sum of each period of the transfusion independence. Platelets transfusions independence period is defined as the period for which participants having received no platelets transfusions during at least 8 consecutive weeks after randomization.	approx. 48 months
Serum Concentrations for MBG453	Pharmacokinetics (PK) of MBG453 when given in combination with hypomethylating agents (HMA)	0hr pre-dose on Day 8 of each cycle until cycle 6 and on Day 8 of cycles 9, 12, 18 and 24, 2hr post-dose on Day 8 of C1 and C3, EOT (approx. 48 months) and up to 150 day of the safety follow up period; 1 cycle = 28 days
Immunogenicity (IG) of MBG453 When Given in Combination of Hypomethylating Agents: ADA Prevalence	Number of participants with at least one sample meeting the criteria at baseline. Anti-drug Antibody (ADA) prevalence equals ADA-positive at baseline.	at baseline
Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents: ADA-positive Participants	Anti-drug Antibody (ADA) positive participants on-treatment was calculated as the number of participants with at least 1 on-treatment ADA-positive sample divided by the number of participants with a determinant baseline IG sample and at least one determinant post-baseline IG sample.	approx. 48 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Zeidan AM, Ando K, Rauzy O, Turgut M, Wang MC, Cairoli R, Hou HA, Kwong YL, Arnan M, Meers S, Pullarkat V, Santini V, Malek K, Kiertsman F, Niolat J, Ramos PM, Menssen HD, Fenaux P, Miyazaki Y, Platzbecker U. Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2024 Jan;11(1):e38-e50. doi: 10.1016/S2352-3026(23)00333-2. Epub 2023 Dec 5.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2019
• Primary Completion (Actual): April 26, 2022
• Study Completion (Actual): July 15, 2024

Study Registration Dates

• First Submitted: May 8, 2019
• First Submitted That Met QC Criteria: May 9, 2019
• First Posted (Actual): May 13, 2019

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: TIM-3; Phase II; MBG453; Placebo; decitabine; azacitidine; myelodysplastic syndrome (MDS); Sabatolimab
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; sabatolimab
• Other Study ID Numbers: CMBG453B12201; 2018-004479-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Sharing Access Criteria

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No