A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants (STIMULUS-MDS3)

A Single-arm, Open-label, Phase II Study of Sabatolimab in Combination With Azacitidine and Venetoclax in Adult Participants With High or Very High Risk Myelodysplastic Syndromes (MDS) as Per IPSS-R Criteria

The purpose of the study was to find out if the new drug sabatolimab when given in combination with azacitidine and venetoclax, was safe and had beneficial effects in participants with high or very high risk myelodysplastic syndrome (MDS) who were not suitable for treatment with intensive chemotherapy or a stem-cell transplant (HSCT).

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndrome (MDS)
• Intervention / Treatment: Drug: sabatolimab; Drug: azacitidine; Drug: venetoclax

Detailed Description

Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years were to be asked to join this study but due to the decision by Novartis to halt recruitment the study did not enroll the approximately 76 participants.

The primary purpose of Part 1 (Safety run-in) was to rule out excessive toxicity of sabatolimab, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) was to have evaluated efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS. But due to the decision by Novartis to halt recruitment at the end of the Safety run-in, the study enrolled participants in Part 1 only.

This study was to have consisted of two parts:

Safety Run-in Part:

The first approximately 18 participants to have joined the study would have been part of the safety run-in. The first approximately 6 participants would have been enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort.

After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with approximately 12 participants, to have been enrolled to the higher dose given every four weeks safety run-in cohort. After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with expansion part of the study.

Expansion Part (which did not occur):

After the safety run-in part would have confirmed that the study treatment (higher dose of sabatolimab given every four weeks with azacitidine and venetoclax) was safe, about 58 more participants would have been enrolled in the expansion part to better investigate the efficacy of the study treatment.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brasschaat, Belgium, 2930
    • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Nice, France, 06202
    • Novartis Investigative Site
• Germany
  • Düsseldorf, Germany, 40479
    • Novartis Investigative Site
  • Stuttgart, Germany, 70376
    • Novartis Investigative Site
• Greece
  • Pátrai, Greece, 265 00
    • Novartis Investigative Site
  • Evros
    • Alexandroupoli, Evros, Greece, 681 00
      • Novartis Investigative Site
• Hungary
  • Nyíregyháza, Hungary, 4400
    • Novartis Investigative Site
• Italy
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08036
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study
2. Age ≥ 18 years at the date of signing the informed consent form (ICF)

3. Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al 2012):

   • Very high (> 6 points)
   • High (> 4.5-6 points)
4. Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability (de Witte et al 2017)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

1. Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including venetoclax) at any time
2. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not allowed if the last dose of the drug was administered within 4 months prior to start of treatment
3. Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R,Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic agents, approved or investigational, including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine However, a one single cycle of HMAs treatment only started prior to enrollment is allowed.
4. Live vaccine administered within 30 days prior to start of treatment
5. Current use or use within 14 days prior to start of treatment 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
6. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
7. Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: sabatolimab + azacitidine + venetoclax; Part 1: Safety run-in consisted of 2 subsequent cohorts of a lower dose (cohort 1) and a higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine. Part 2 (did not start as recruitment was stopped in Part 1) Expansion was to enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose was to have been combined to determine the complete remission rate.

Drug: sabatolimab; Sabatolimab was administered at a low dose (Safety run-in (Part 1) cohort 1) or a high dose (Safety run-in (Part 1) cohort 2) via i.v. infusion over 30 minutes on Day 8 of every treatment cycle. Cycle = 28 days; Other Names: MBG453; Drug: azacitidine; A standard dose of azacitidine was given subcutaneously or intravenously every day for seven consecutive days on days 1-7 of a confirmed treatment cycle. In keeping with standard clinical practice, the alternative schedules for five consecutive days on days 1-5, followed by a two day break, then two consecutive days on days 8-9 was permitted (alternative schedule).; Drug: venetoclax; Venetoclax film-coated tablets was administered at a dose of 400 mg orally or corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong CYP3A4 inhibitors, once a day, from C1D1 to C1D14 during the treatment cycle. No ramp-up for venetoclax was necessary.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Dose Limiting Toxicities (DLTs) - All Grades (Safety run-in Patients Only)	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibly related to sabatolimab as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets severity criteria as per protocol.	From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
Percentage of Participants (Receiving 800mg Sabatolimab) Achieving Complete Remission (CR) Per Investigator Assessment	This endpoint assessed Complete Remission (CR) Rate of participants from Cohort 2 of Part 1 and Part 2 according to Investigator assessment per modified IWG-MDS - Cheson 2006 criteria. CR is defined as follows: bone marrow blasts <=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence of blasts in peripheral blood.	up to approx. 23 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Achieving a Complete Remission (CR) + Morphologic Complete Remission (mCR): Safety run-in (Part 1)	Assessed the durability of complete remission (CR) or morphologic complete remission (mCR) rate. mCR is defined as <=5% blasts and blast count decrease by >=50% compared to baseline as per modified IWG-MDS Cheson 2006 criteria.	up to approx. 23 months
Overall Response Rate (ORR) of Participants Who Achieved Hematologic Improvement (HI) or Better as Best Response	The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria. Partial response (PR): all complete response (CR) criteria except >=50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow >5%. HI (erythroid response or platelet response or neutrophil response) must last at least 8 weeks.	up to approx. 23 months
Percentage of Participants Who Are RBC/Platelets Transfusion Independent	Improvement in red blood cells (RBC)/platelets transfusion post-baseline as per International Working Group - Myelodysplastic syndromes (IWG-MDS) by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (Cohort 2 of safety run-in and expansion parts). RBC/Platelets transfusion independence is defined as participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks after start of treatment.	up to approx. 23 months
Duration of Transfusion Independence	Sum of each period of the transfusion independence for participants with at least one period of transfusion independence post-baseline by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (Cohort 2 of safety run-in and expansion parts) for both red blood cells and platelets. RBC/Platelets transfusion independence is defined as participants having received no RBC/platelets transfusions during at least 8 consecutive weeks after start of treatment.	up to approx. 23 months
Peak Serum Concentration (Cmax) of Sabatolimab	Maximal concentration of sabatolimab for participants treated with sabatolimab by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)).	Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
Trough Serum Concentration (Cmin) Sabatolimab	Concentration of sabatolimab prior to next dosing or after end of treatment by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)).	Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Incidence On-treatment by Dose Level	Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment	Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
Duration of Complete Remission (CR)	Duration of complete remission (CR) is defined as time from first occurrence of CR to relapse from CR, progression or death due to any cause whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)). CR is defined as follows: bone marrow blasts <=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence of blasts in peripheral blood. Relapse from complete remission (CR)is when at least 1 of the following criteria is met: Return to baseline bone marrow blast percentage.; Decrease of ≥ 50% from maximum remission/response levels in neutrophils AND neutrophils <1.0*10^9/L.; Decrease of ≥ 50% from maximum remission/response levels in platelets AND platelets <100*10^9/L.; Decrease from maximum remission/response levels in Hgb concentration by ≥ 1.5g/dL AND Hgb < 10g/dL.; Becoming transfusion dependent	up to approx. 23 months
Time to Complete Remission(CR)/Marrow Complete Remission (mCR)	Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Duration of Complete Response (CR)/Marrow Complete Response (mCR)	Duration of CR/mCR is defined as time from first occurrence of CR/mCR to relapse from CR, progression or death due to any cause whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Duration of Response for Participants Who Achieved Hematologic Improvement (HI) or Better	The duration of response was derived for participants treated with sabatolimab at the higher dose who achieved HI or better as per investigator assessment and is defined from the first occurrence of complete response (CR), marrow complete response (mCR), partial response (PR) or hematologic improvement (HI) until relapse, progression or death due to any reason for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Progression-Free Survival (PFS)	Time from start of treatment to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR or death due to any cause, whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Leukemia-Free Survival (LFS)	Time from start of treatment to transformation to acute leukemias per investigator assessment [as defined as ≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause, whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Event-Free Survival (EFS)	Time from start of treatment to lack of reaching CR within the first 6 cycles, relapse from CR or death due to any cause, whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Overall Survival (OS)	Time from start of treatment to death due to any cause for the safety run-in part (Cohort 2 (800 mg Q4W)).	Date of start of treatment to date of death due to any reason, for up to approx. 23 months
Changes in Fatigue (Part 2 - Expansion)	Changes in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue for participants treated with sabatolimab at the higher dose of the expansion part only. Measurements would have been taken via scores from 0 (not at all) to 4 (very much). The higher the score, the better the Quality of Life.	throughout study until progressive disease, death or study discontinuation, approx. 3 years

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2021
• Primary Completion (Actual): May 8, 2023
• Study Completion (Actual): May 8, 2023

Study Registration Dates

• First Submitted: February 23, 2021
• First Submitted That Met QC Criteria: March 19, 2021
• First Posted (Actual): March 23, 2021

Study Record Updates

• Last Update Posted (Estimated): October 9, 2025
• Last Update Submitted That Met QC Criteria: September 29, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: MDS; TIM-3; Phase II; venetoclax; Myelodysplastic syndrome; sabatolimab; azacitidine; MGM453
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; sabatolimab
• Other Study ID Numbers: CMBG453B12203; 2020-003669-21 (EudraCT Number)

Plan for Individual participant data (IPD)

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

IPD Plan Description

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